TRC8 N-terminal domain; This region is found at the N-terminus of the TRC8 protein. TRC8 is an E3 ubiquitin-protein ligase also known as RNF139. This region contains 12 transmembrane domains. This region has been suggested to contain a sterol sensing domain. It has been found that TRC8 protein levels are sterol responsive and that it binds and stimulates ubiquitylation of the endoplasmic reticulum anchor protein INSIG.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221044924   22 EAVLNVALRVPSIMLLDVLYRWDVSsffqqIQRSSLSNNPLFQYkylalnmhyVGYILSVVLLTLPRQHLVQLYLYFLTA 101
Cdd:pfam13705   1 LAVLDVALRVPPLFIIDELLNSDFG-----LPSFLTSVKILLSY---------LGFFVSLVVLLLPTRHLIKLYLHLLSA 66

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221044924  102 LLLYAGHQISRDYV---RSELEFAYEGPMYLEPLSMNRFTTALIGQLVVCTLCSCVMKTK-----QIWLFSAHMLPLLAR 173
Cdd:pfam13705  67 GLVLVSYWANVDYVlnfSSELESAYFGLLLLPNNGPTRFVTALILQLILSTLFSYLHLGPrnpiiQKWLFLAFLLPLLAR 146

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221044924  174 LCLVPLETIVIINKFAMIFTGLEVLYFLGSNLLVPYNLAKSAYRELVQVVEVYGLLALGMSLWNQLVVPVLFMVFWLVLF 253
Cdd:pfam13705 147 LPDLPLDVLKTLPVFAALLPLVEVLYFLWSNLFVPYNLIKYAYRHIRNFIRVYGLSALVESLWKRLNVPSVLRVFWLIRF 226

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221044924  254 ALQIYSYFSTRDQPASrERLLFLFLTSIAECCSTPYSLLGLVFTVSFVALGVLTLCKFYLQGYRAFMNDpamNRGMTEGV 333
Cdd:pfam13705 227 LEQLYLLLYDVEISES-QGLLGLLLTLLIEGCDTPTAVLGMTSVVSYIAHYIGLLFKWYLLGSDAEEDK---NRGTVEAV 302

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221044924  334 TLLILAVQTGLIELQVVHRAFLLSIILFIVVASILQSMLEIADPIVLALGASRDKSLWKHFRAVSLCLFLLVFPAYMAYM 413
Cdd:pfam13705 303 LFLILALQTGLTGLQPEQRFVRLSRNLCLLLTALLHFIHEIVDPVLLSLSASHNPSLWRHFRALLVCLFLIVFPVFLLYY 382

                         410       420       430       440       450       460       470       480
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221044924  414 ICQFFHMDFWLLIIISSSILTSLQVLGTLFIYVLFMVEEFRKEPVENMDDVIYYVNGTYRLLEFLVALCVVAYGVSETIF 493
Cdd:pfam13705 383 LWSFFPLDTWLLAVTAFCIETSLKVLVSLAVYSLFMIDAYRSTPWEKLDDYVYYVRATGNVIEFIFGIFVFGNGAWELLF 462

                         490       500
                  ....*....|....*....|....*..
gi 221044924  494 GEWTVMGSMIIFIHSYYNVWLRAQLGW 520
Cdd:pfam13705 463 ESGSWIRASMMCIHAYFNIWLRAQAGW 489

HRD ubiquitin ligase complex, ER membrane component [Posttranslational modification, protein turnover, chaperones];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221044924 534 KSLPIATKEQLEKHNDICAICYQDM-------------KSAVITPCSHFFHAGCLKKWLYVQETCPLChchlknssQLPG 600
Cdd:COG5243  273 AMYPTATEEQLTNSDRTCTICMDEMfhpdheplprgldMTPKRLPCGHILHLHCLKNWLERQQTCPIC--------RRPV 344

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|..
gi 221044924 601 LGTE--PVLQ-PHAGAEqnvmfQEGTEPPGQEHTPGTRIQEG 639
Cdd:COG5243  345 IFDQssPTPAsPNVRNT-----QIATQVPNPDNTPTTTAVPG 381

TRC8 N-terminal domain; This region is found at the N-terminus of the TRC8 protein. TRC8 is an E3 ubiquitin-protein ligase also known as RNF139. This region contains 12 transmembrane domains. This region has been suggested to contain a sterol sensing domain. It has been found that TRC8 protein levels are sterol responsive and that it binds and stimulates ubiquitylation of the endoplasmic reticulum anchor protein INSIG.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221044924   22 EAVLNVALRVPSIMLLDVLYRWDVSsffqqIQRSSLSNNPLFQYkylalnmhyVGYILSVVLLTLPRQHLVQLYLYFLTA 101
Cdd:pfam13705   1 LAVLDVALRVPPLFIIDELLNSDFG-----LPSFLTSVKILLSY---------LGFFVSLVVLLLPTRHLIKLYLHLLSA 66

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221044924  102 LLLYAGHQISRDYV---RSELEFAYEGPMYLEPLSMNRFTTALIGQLVVCTLCSCVMKTK-----QIWLFSAHMLPLLAR 173
Cdd:pfam13705  67 GLVLVSYWANVDYVlnfSSELESAYFGLLLLPNNGPTRFVTALILQLILSTLFSYLHLGPrnpiiQKWLFLAFLLPLLAR 146

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221044924  174 LCLVPLETIVIINKFAMIFTGLEVLYFLGSNLLVPYNLAKSAYRELVQVVEVYGLLALGMSLWNQLVVPVLFMVFWLVLF 253
Cdd:pfam13705 147 LPDLPLDVLKTLPVFAALLPLVEVLYFLWSNLFVPYNLIKYAYRHIRNFIRVYGLSALVESLWKRLNVPSVLRVFWLIRF 226

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221044924  254 ALQIYSYFSTRDQPASrERLLFLFLTSIAECCSTPYSLLGLVFTVSFVALGVLTLCKFYLQGYRAFMNDpamNRGMTEGV 333
Cdd:pfam13705 227 LEQLYLLLYDVEISES-QGLLGLLLTLLIEGCDTPTAVLGMTSVVSYIAHYIGLLFKWYLLGSDAEEDK---NRGTVEAV 302

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221044924  334 TLLILAVQTGLIELQVVHRAFLLSIILFIVVASILQSMLEIADPIVLALGASRDKSLWKHFRAVSLCLFLLVFPAYMAYM 413
Cdd:pfam13705 303 LFLILALQTGLTGLQPEQRFVRLSRNLCLLLTALLHFIHEIVDPVLLSLSASHNPSLWRHFRALLVCLFLIVFPVFLLYY 382

                         410       420       430       440       450       460       470       480
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221044924  414 ICQFFHMDFWLLIIISSSILTSLQVLGTLFIYVLFMVEEFRKEPVENMDDVIYYVNGTYRLLEFLVALCVVAYGVSETIF 493
Cdd:pfam13705 383 LWSFFPLDTWLLAVTAFCIETSLKVLVSLAVYSLFMIDAYRSTPWEKLDDYVYYVRATGNVIEFIFGIFVFGNGAWELLF 462

                         490       500
                  ....*....|....*....|....*..
gi 221044924  494 GEWTVMGSMIIFIHSYYNVWLRAQLGW 520
Cdd:pfam13705 463 ESGSWIRASMMCIHAYFNIWLRAQAGW 489

Ring finger domain;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 221044924  549 DICAICYQDMK---SAVITPCSHFFHAGCLKKWLYVQETCPLC 588
Cdd:pfam13639   1 DECPICLEEFEegdKVVVLPCGHHFHRECLDKWLRSSNTCPLC 43

HRD ubiquitin ligase complex, ER membrane component [Posttranslational modification, protein turnover, chaperones];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221044924 534 KSLPIATKEQLEKHNDICAICYQDM-------------KSAVITPCSHFFHAGCLKKWLYVQETCPLChchlknssQLPG 600
Cdd:COG5243  273 AMYPTATEEQLTNSDRTCTICMDEMfhpdheplprgldMTPKRLPCGHILHLHCLKNWLERQQTCPIC--------RRPV 344

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|..
gi 221044924 601 LGTE--PVLQ-PHAGAEqnvmfQEGTEPPGQEHTPGTRIQEG 639
Cdd:COG5243  345 IFDQssPTPAsPNVRNT-----QIATQVPNPDNTPTTTAVPG 381

DNA repair protein rad18; All proteins in this family for which functions are known are involved in nucleotide excision repair.This family is based on the phylogenomic analysis of JA Eisen (1999, Ph.D. Thesis, Stanford University). [DNA metabolism, DNA replication, recombination, and repair]

                          10        20        30
                  ....*....|....*....|....*....|....*...
gi 221044924  551 CAICYQDMKSAVITPCSHFFHAGCLKKWLYVQETCPLC 588
Cdd:TIGR00599  29 CHICKDFFDVPVLTSCSHTFCSLCIRRCLSNQPKCPLC 66

TRC8 N-terminal domain; This region is found at the N-terminus of the TRC8 protein. TRC8 is an E3 ubiquitin-protein ligase also known as RNF139. This region contains 12 transmembrane domains. This region has been suggested to contain a sterol sensing domain. It has been found that TRC8 protein levels are sterol responsive and that it binds and stimulates ubiquitylation of the endoplasmic reticulum anchor protein INSIG.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221044924   22 EAVLNVALRVPSIMLLDVLYRWDVSsffqqIQRSSLSNNPLFQYkylalnmhyVGYILSVVLLTLPRQHLVQLYLYFLTA 101
Cdd:pfam13705   1 LAVLDVALRVPPLFIIDELLNSDFG-----LPSFLTSVKILLSY---------LGFFVSLVVLLLPTRHLIKLYLHLLSA 66

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221044924  102 LLLYAGHQISRDYV---RSELEFAYEGPMYLEPLSMNRFTTALIGQLVVCTLCSCVMKTK-----QIWLFSAHMLPLLAR 173
Cdd:pfam13705  67 GLVLVSYWANVDYVlnfSSELESAYFGLLLLPNNGPTRFVTALILQLILSTLFSYLHLGPrnpiiQKWLFLAFLLPLLAR 146

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221044924  174 LCLVPLETIVIINKFAMIFTGLEVLYFLGSNLLVPYNLAKSAYRELVQVVEVYGLLALGMSLWNQLVVPVLFMVFWLVLF 253
Cdd:pfam13705 147 LPDLPLDVLKTLPVFAALLPLVEVLYFLWSNLFVPYNLIKYAYRHIRNFIRVYGLSALVESLWKRLNVPSVLRVFWLIRF 226

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221044924  254 ALQIYSYFSTRDQPASrERLLFLFLTSIAECCSTPYSLLGLVFTVSFVALGVLTLCKFYLQGYRAFMNDpamNRGMTEGV 333
Cdd:pfam13705 227 LEQLYLLLYDVEISES-QGLLGLLLTLLIEGCDTPTAVLGMTSVVSYIAHYIGLLFKWYLLGSDAEEDK---NRGTVEAV 302

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221044924  334 TLLILAVQTGLIELQVVHRAFLLSIILFIVVASILQSMLEIADPIVLALGASRDKSLWKHFRAVSLCLFLLVFPAYMAYM 413
Cdd:pfam13705 303 LFLILALQTGLTGLQPEQRFVRLSRNLCLLLTALLHFIHEIVDPVLLSLSASHNPSLWRHFRALLVCLFLIVFPVFLLYY 382

                         410       420       430       440       450       460       470       480
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221044924  414 ICQFFHMDFWLLIIISSSILTSLQVLGTLFIYVLFMVEEFRKEPVENMDDVIYYVNGTYRLLEFLVALCVVAYGVSETIF 493
Cdd:pfam13705 383 LWSFFPLDTWLLAVTAFCIETSLKVLVSLAVYSLFMIDAYRSTPWEKLDDYVYYVRATGNVIEFIFGIFVFGNGAWELLF 462

                         490       500
                  ....*....|....*....|....*..
gi 221044924  494 GEWTVMGSMIIFIHSYYNVWLRAQLGW 520
Cdd:pfam13705 463 ESGSWIRASMMCIHAYFNIWLRAQAGW 489

RING finger, H2 subclass, found in RING finger proteins RNF139, RNF145, and similar proteins; RNF139, also known as translocation in renal carcinoma on chromosome 8 protein (TRC8), is an endoplasmic reticulum (ER)-resident multi-transmembrane protein that functions as a potent growth suppressor in mammalian cells, inducing G2/M arrest, decreased DNA synthesis and increased apoptosis. It is a tumor suppressor that has been implicated in a novel regulatory relationship linking the cholesterol/lipid biosynthetic pathway with cellular growth control. A mutation in RNF139 has been identified in families with hereditary renal (RCC) and thyroid cancers. RNF145 is an uncharacterized RING finger protein encoded by the RNF145 gene, which is expressed in T lymphocytes, and its expression is altered in acute myelomonocytic and acute promyelocytic leukemias. Although its biological function remains unclear, RNF145 shows high sequence similarity with RNF139. Both RNF139 and RNF145 contain a C3H2C3-type RING-H2 finger with possible E3-ubiquitin ligase activity.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|.
gi 221044924 549 DICAICYQDMKSAVITPCSHFFHAGCLKKWLYVQETCPLCH 589
Cdd:cd16476    1 DVCAICYQEMKEARITPCNHFFHGLCLRKWLYVQDTCPLCH 41

RING finger, H2 subclass, found in Saccharomyces cerevisiae transmembrane E3 ubiquitin-protein ligase 1 (TUL1) and similar proteins; This subfamily includes Saccharomyces cerevisiae TUL1, Schizosaccharomyces pombe DSC E3 ubiquitin ligase complex subunit 1 (DSC1), and Arabidopsis thaliana protein FLYING SAUCER 2 (FLY2). TUL1 is the catalytic component of DSC E3 ubiquitin ligase complexes that tag proteins present in Golgi, endosome and vacuole membranes and function in protein homeostasis under non-stress conditions, and support a role in protein quality control. It mediates ubiquitination of vacuolar proteins such as CPS1, PPN1, PEP12 and other proteins containing exposed hydrophilic residues within their transmembrane domains, leading to their sorting into internal vesicles in late endosomes. TUL1 also targets the unpalmitoylated endosomal SNARE TLG1 to the multivesicular body (MVB) pathway. DSC1, also known as defective for SREBP cleavage protein 1, is the catalytic component of the DSC E3 ubiquitin ligase complex required for the sre1 transcriptional activator proteolytic cleavage to release the soluble transcription factor from the membrane in low oxygen or sterol conditions. FLY2 acts as an E3 ubiquitin-protein ligase that may be involved in xylem development. Members of this subfamily contain a C3H2C3-type RING-H2 finger.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 221044924 550 ICAICYQDM---------KSAVITPCSHFFHAGCLKKWLYVQETCPLCHCHL 592
Cdd:cd23117    6 DCVICMSDIelpstnsvrRDYMVTPCNHIFHTNCLERWMDIKLECPTCRRPL 57

H2 subclass of RING (RING-H2) fingers and its variants; The RING finger is a specialized type of Zn-finger of 40 to 60 residues that binds two atoms of zinc. It is defined by the "cross-brace" motif that chelates zinc atoms by eight amino acid residues, typically Cys or His, arranged in a characteristic spacing. Canonical RING motifs have been categorized into two major subclasses, RING-HC (C3HC4-type) and RING-H2 (C3H2C3-type), according to their Cys/His content. There are also many variants of RING fingers: some have different Cys/His patterns while some lack a single Cys or His residue at typical Zn ligand positions (the fourth or eighth zinc ligand is prevalently exchanged for an Asp, which can indeed chelate Zn in a RING finger as well). This family corresponds to the H2 subclass of RING (RING-H2) finger proteins that are characterized by containing C3H2C3-type canonical RING-H2 fingers or noncanonical RING-H2 finger variants, including C4HC3- (RING-CH alias RINGv), C3H3C2-, C3H2C2D-, C3DHC3-, and C4HC2H-type modified RING-H2 fingers. The canonical RING-H2 finger has been defined as C-X2-C-X(9-39)-C-X(1-3)-H-X(2-3)-H-X2-C-X(4-48)-C-X2-C, X is any amino acid and the number of X residues varies in different fingers. It binds two Zn ions in a unique "cross-brace" arrangement, which distinguishes it from tandem zinc fingers and other similar motifs. RING-H2 finger can be found in a group of diverse proteins with a variety of cellular functions, including oncogenesis, development, viral replication, signal transduction, the cell cycle and apoptosis. Many of them are ubiquitin-protein ligases (E3s) that serves as a scaffold for binding to ubiquitin-conjugating enzymes (E2s, also referred to as ubiquitin carrier proteins or UBCs) in close proximity to substrate proteins, which enables efficient transfer of ubiquitin from E2 to the substrates.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|...
gi 221044924 551 CAICYQDMKS---AVITPCSHFFHAGCLKKWL-YVQETCPLCH 589
Cdd:cd16448    1 CVICLEEFEEgdvVRLLPCGHVFHLACILRWLeSGNNTCPLCR 43

RING finger, H2 subclass, found in RING finger proteins RNF24, RNF122, and similar proteins; This subfamily includes RNF24, RNF122, and similar proteins. RNF24 is an intrinsic membrane protein localized in the Golgi apparatus. It specifically interacts with the ankyrin-repeats domains (ARDs) of TRPC1, -3, -4, -5, -6, and -7, and affects TRPC intracellular trafficking without affecting their activity. RNF122 is a RING finger protein associated with HEK 293T cell viability. It is localized to the endoplasmic reticulum (ER) and the Golgi apparatus, and overexpressed in anaplastic thyroid cancer cells. RNF122 functions as an E3 ubiquitin ligase that can ubiquitinate itself and undergo degradation through its RING finger in a proteasome-dependent manner. Both RNF24 and RNF122 contain an N-terminal transmembrane domain and a C-terminal C3H2C3-type RING-H2 finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|...
gi 221044924 549 DICAICYQDMK---SAVITPCSHFFHAGCLKKWLYVQETCPLC 588
Cdd:cd16469    1 DTCAVCLEEFKlkeELGVCPCGHAFHTKCLKKWLEVRNSCPIC 43

RING finger, H2 subclass, found in the PA-TM-RING ubiquitin ligase family; The PA-TM-RING family represents a group of transmembrane-type E3 ubiquitin ligases, which has been characterized by an N-terminal transient signal peptide, a PA (protease-associated) domain, a TM (transmembrane) domain, as well as a C-terminal C3H2C3-type RING-H2 finger domain. It includes RNF13, RNF167, ZNRF4 (zinc and RING finger 4), GRAIL (gene related to anergy in lymphocytes)/RNF128, RNF130, RNF133, RNF148, RNF149 and RNF150 (which are more closely related), as well as RNF43 and ZNRF3, which have substantially longer C-terminal tail extensions compared with the others. PA-TM-RING proteins are expressed at low levels in all mammalian tissues and species, but they are not present in yeast. They play a common regulatory role in intracellular trafficking/sorting, suggesting that abrogation of their function may result in dysregulation of cellular signaling events in cancer.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|.
gi 221044924 551 CAICYQDMKSAVIT---PCSHFFHAGCLKKWLYVQETCPLC 588
Cdd:cd16454    2 CAICLEEFKEGEKVrvlPCNHLFHKDCIDPWLEQHNTCPLC 42

RING finger, H2 subclass, found in RING finger protein 24 (RNF24) and similar proteins; RNF24 is an intrinsic membrane protein localized in the Golgi apparatus. It specifically interacts with the ankyrin-repeats domains (ARDs) of TRPC1, -3, -4, -5, -6, and -7, and affects TRPC intracellular trafficking without affecting their activity. RNF24 contains an N-terminal transmembrane domain and a C-terminal C3H2C3-type RING-H2 finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....
gi 221044924 549 DICAICYQDMKSA---VITPCSHFFHAGCLKKWLYVQETCPLCH 589
Cdd:cd16675    1 EICAVCLEEFKPKdelGICPCKHAFHRKCLIKWLEVRKVCPLCN 44

RING finger, H2 subclass, found in RING finger protein 44 (RNF44) and similar proteins; RNF44 is an uncharacterized RING finger protein that shows high sequence similarity with RNF38, which is a nuclear E3 ubiquitin protein ligase that plays a role in regulating p53. RNF44 contains a coiled-coil motif, a KIL motif (Lys-X2-Ile/Leu-X2-Ile/Leu, X can be any amino acid), and a C3H2C2-type RING-H2 finger.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 221044924 542 EQLEKHNDICAICYQDMKSAV---ITPCSHFFHAGCLKKWLYVQETCPLCHChlkNSSQLP 599
Cdd:cd16680    1 ENHQSEQTLCVVCFSDFESRQllrVLPCNHEFHTKCVDKWLKTNRTCPICRA---DASEVH 58

RING finger, H2 subclass, found in RING finger protein 122 (RNF122) and similar proteins; RNF122 is a RING finger protein associated with HEK 293T cell viability. It is localized to the endoplasmic reticulum (ER) and the Golgi apparatus, and overexpressed in anaplastic thyroid cancer cells. RNF122 functions as an E3 ubiquitin ligase that can ubiquitinate itself and undergo degradation through its RING finger in a proteasome-dependent manner. It interacts with calcium-modulating cyclophilin ligand (CAML), which is not a substrate, but a stabilizer of RNF122. RNF122 contains an N-terminal transmembrane domain and a C-terminal C3H2C3-type RING-H2 finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|..
gi 221044924 551 CAICYQDMKSAV---ITPCSHFFHAGCLKKWLYVQETCPLCH 589
Cdd:cd16676    3 CAVCLEDFKTKDelgVLPCQHAFHRKCLVKWLEIRCVCPMCN 44

Ring finger; E3 ubiquitin-protein ligase activity is intrinsic to the RING domain of c-Cbl and is likely to be a general function of this domain; Various RING fingers exhibit binding activity towards E2 ubiquitin-conjugating enzymes (Ubc' s)

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|
gi 221044924   551 CAICYQDM-KSAVITPCSHFFHAGCLKKWLYVQE-TCPLC 588
Cdd:smart00184   1 CPICLEEYlKDPVILPCGHTFCRSCIRKWLESGNnTCPIC 40

RING finger, H2 subclass, found in RING finger proteins RNF126, RNF115, and similar proteins; This subfamily includes RING finger proteins RNF126, RNF115, and similar proteins. RNF126 is a Bag6-dependent E3 ubiquitin ligase that is involved in the mislocalized protein (MLP) pathway of quality control. It regulates the retrograde sorting of the cation-independent mannose 6-phosphate receptor (CI-MPR). RNF126 promotes cancer cell proliferation by targeting the tumor suppressor p21 for ubiquitin-mediated degradation, and could be a novel therapeutic target in breast and prostate cancers. It is also able to ubiquitylate cytidine deaminase (AID), a poorly soluble protein that is essential for antibody diversification. RNF115, also known as Rab7-interacting ring finger protein (Rabring 7), or zinc finger protein 364 (ZNF364), or breast cancer-associated gene 2 (BCA2), is an E3 ubiquitin-protein ligase that is an endogenous inhibitor of adenosine monophosphate-activated protein kinase (AMPK) activation; this inhibition increases the efficacy of metformin in breast cancer cells. It also functions as a cofactor in the restriction imposed by tetherin on HIV-1, and targets HIV-1 Gag for lysosomal degradation, impairing virus assembly and release, in a tetherin-independent manner. Moreover, RNF115 is a Rab7-binding protein that stimulates c-Myc degradation through mono-ubiquitination of MM-1. It also plays crucial roles as a Rab7 target protein in vesicle traffic to late endosome/lysosome and lysosome biogenesis. RNF115 and RNF126 associate with the epidermal growth factor receptor (EGFR) and promote ubiquitylation of EGFR, suggesting they play a role in the ubiquitin-dependent sorting and downregulation of membrane receptors. Both of them contain an N-terminal BCA2 Zinc-finger domain (BZF), AKT-phosphorylation sites, and a C-terminal C3H2C3-type RING-H2 finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|.
gi 221044924 551 CAICYQDMK---SAVITPCSHFFHAGCLKKWLYVQETCPLC 588
Cdd:cd16667    2 CAVCKEDFEvgeEVRQLPCKHLFHPDCIVPWLELHNSCPVC 42

RING finger, H2 subclass, found in RING finger protein 167 (RNF167) and similar proteins; RNF167, also known as RING105, is an endosomal/lysosomal E3 ubiquitin-protein ligase involved in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) ubiquitination. It ubiquitinates AMPA-type glutamate receptor subunit GluA2 and regulates its surface expression, and thus acts as a selective regulator of AMPAR-mediated neurotransmission. It acts as an endosomal membrane protein which ubiquitylates vesicle-associated membrane protein 3 (VAMP3) and regulates endosomal trafficking. Moreover, RNF167 plays a role in the regulation of TSSC5 (tumor-suppressing subchromosomal transferable fragment cDNA, also known as ORCTL2/IMPT1/BWR1A/SLC22A1L), which can function in concert with the ubiquitin-conjugating enzyme UbcH6. RNF167 is widely conserved in metazoans and contains an N-terminal signal peptide, a protease-associated (PA) domain, two transmembrane domains (TM1 and TM2), and a C-terminal C3H2C3-type RING-H2 finger domain followed by a putative PEST sequence.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....
gi 221044924 549 DICAIC---YQDMKSAVITPCSHFFHAGCLKKWLY-VQETCPLC 588
Cdd:cd16797    1 DVCAICldeYEEGDKLRVLPCSHAYHSKCVDPWLTqTKKTCPVC 44

RING finger, H2 subclass, found in RING finger protein 115 (RNF115) and similar proteins; RNF115, also known as Rab7-interacting ring finger protein (Rabring 7), or zinc finger protein 364 (ZNF364), or breast cancer-associated gene 2 (BCA2), is an E3 ubiquitin-protein ligase that is an endogenous inhibitor of adenosine monophosphate-activated protein kinase (AMPK) activation and its inhibition increases the efficacy of metformin in breast cancer cells. It also functions as a co-factor in the restriction imposed by tetherin on HIV-1, and targets HIV-1 Gag for lysosomal degradation, impairing virus assembly and release, in a tetherin-independent manner. Moreover, RNF115 is a Rab7-binding protein that stimulates c-Myc degradation through mono-ubiquitination of MM-1. It also plays crucial roles as a Rab7 target protein in vesicle traffic to late endosome/lysosome and lysosome biogenesis. Furthermore, RNF115 and the related protein, RNF126 associate with the epidermal growth factor receptor (EGFR) and promote ubiquitylation of EGFR, suggesting they play a role in the ubiquitin-dependent sorting and downregulation of membrane receptors. RNF115 contains an N-terminal BCA2 Zinc-finger domain (BZF), the AKT-phosphorylation sites, and the C-terminal C3H2C3-type RING-H2 finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|.
gi 221044924 551 CAICYQDMKSAVIT---PCSHFFHAGCLKKWLYVQETCPLC 588
Cdd:cd16800    3 CPVCKEDYTVGEQVrqlPCNHFFHSDCIVPWLELHDTCPVC 43

RING finger, H2 subclass, found in RING finger protein 128 (RNF128) and similar proteins; This subfamily includes RING finger proteins RNF128, RNF133, RNF148, and similar proteins, which belong to a larger PA-TM-RING ubiquitin ligase family that has been characterized by containing an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C-terminal C3H2C3-type RING-H2 finger followed by a putative PEST sequence. RNF128, also known as gene related to anergy in lymphocytes protein (GRAIL), is a type 1 transmembrane E3 ubiquitin-protein ligase that is a critical regulator of adaptive immunity and development. It inhibits cytokine gene transcription, is expressed in anergic CD4+ T cells, and has been implicated in primary T cell activation, survival, and differentiation, as well as in T cell anergy and oral tolerance. It induces T cell anergy through the ubiquitination activity of its cytosolic RING finger. It regulates expression of the costimulatory molecule CD40L on CD4 T cells, and ubiquitinates the costimulatory molecule CD40 ligand (CD40L) during the induction of T cell anergy. Moreover, RNF128 interacts with the luminal/extracellular portion of both CD151 and the related tetraspanin CD81 via its PA domain, which promoted ubiquitination of cytosolic lysine residues. It also down-modulates the expression of CD83 (previously described as a cell surface marker for mature dendritic cells) on CD4 T cells. Furthermore, Rho guanine dissociation inhibitor (RhoGDI) has been identified as a potential substrate of RNF128, suggesting a role for Rho effector molecules in T cell anergy. In addition, RNF128 plays a role in environmental stress responses. It promotes environmental salinity tolerance in euryhaline tilapia. RNF133 is a testis-specific endoplasmic reticulum-associated E3 ubiquitin ligase that is mainly present in the cytoplasm of elongated spermatids. It may play a role in sperm maturation through an ER-associated degradation (ERAD) pathway. RNF148 is a testis-specific E3 ubiquitin ligase that is abundantly expressed in testes and slightly expressed in pancreas. Its expression is regulated by histone deacetylases.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*
gi 221044924 549 DICAIC---YQDMKSAVITPCSHFFHAGCLKKWLYVQETCPLCHC 590
Cdd:cd16802    1 DSCAVCiepYKPNDVVRILTCNHLFHKNCIDPWLLEHRTCPMCKC 45

HRD ubiquitin ligase complex, ER membrane component [Posttranslational modification, protein turnover, chaperones];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221044924 534 KSLPIATKEQLEKHNDICAICYQDM-------------KSAVITPCSHFFHAGCLKKWLYVQETCPLChchlknssQLPG 600
Cdd:COG5243  273 AMYPTATEEQLTNSDRTCTICMDEMfhpdheplprgldMTPKRLPCGHILHLHCLKNWLERQQTCPIC--------RRPV 344

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|..
gi 221044924 601 LGTE--PVLQ-PHAGAEqnvmfQEGTEPPGQEHTPGTRIQEG 639
Cdd:COG5243  345 IFDQssPTPAsPNVRNT-----QIATQVPNPDNTPTTTAVPG 381

RING finger, H2 subclass, found in rice E3 ubiquitin-protein ligase EL5 and similar proteins; EL5, also known as protein ELICITOR 5, is an E3 ubiquitin-protein ligase containing an N-terminal transmembrane domain and a C3H2C3-type RING-H2 finger that is a binding site for ubiquitin-conjugating enzyme (E2). It can be rapidly induced by N-acetylchitooligosaccharide elicitor. EL5 catalyzes polyubiquitination via the Lys48 residue of ubiquitin, and thus plays a crucial role as a membrane-anchored E3 in the maintenance of cell viability after the initiation of root primordial formation in rice. It also acts as an anti-cell death enzyme that might be responsible for mediating the degradation of cytotoxic proteins produced in root cells after the actions of phytohormones. Moreover, EL5 interacts with UBC5b, a rice ubiquitin carrier protein, through its RING-H2 finger. EL5 is an unstable protein, and its degradation is regulated by the C3H2C3-type RING-H2 finger in a proteasome-independent manner.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|...
gi 221044924 550 ICAIC---YQDMKSAVITP-CSHFFHAGCLKKWLYVQETCPLC 588
Cdd:cd16461    1 ECAIClsdYENGEELRRLPeCKHAFHKECIDEWLKSNSTCPLC 43

RING finger, H2 subclass, found in Arabidopsis thaliana RING-type E3 ubiquitin transferase BIG BROTHER (BB) and similar proteins; BB (also known as protein ENHANCER OF DA1-1 or EOD1) is an E3 ubiquitin-protein ligase that limits organ size, and possibly seed size, in a dose-dependent manner. It negatively regulates the duration of cell proliferation in leaves and petals independently of the major phytohormones (e.g. auxin, cytokinin, gibberellin, brassinosteroids, ethylene, abscisic acid, jasmonic acid), probably by targeting growth stimulators for degradation. It limits the proliferation of root meristematic cells. BB polyubiquitinates DA1. It is involved in the promotion of leaf senescence, in addition to its function in restricting plant growth. BB-related is an E3 ubiquitin-ligase probably involved in organ size regulation. Members of this subfamily contain a C3H2C3-type RING-H2 finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....
gi 221044924 548 NDICAIC---YQDMKSAVITPCSHFFHAGCLKKWLYVQETCPLC 588
Cdd:cd23115    4 NERCVICrleYEEGEDLLTLPCKHCYHSECIQQWLQINKVCPVC 47

RING finger, HC subclass, found in RING finger protein RNF5, RNF185 and similar proteins; RNF5 and RNF185 are E3 ubiquitin-protein ligases that are anchored to the outer membrane of the endoplasmic reticulum (ER). RNF5 acts at early stages of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) biosynthesis, and functions as a target for therapeutic modalities to antagonize mutant CFTR proteins in CF patients carrying the F508del allele. RNF185 controls the degradation of CFTR and CFTR F508del allele in a RING- and proteasome-dependent manner, but does not control that of other classical endoplasmic reticulum-associated degradation (ERAD) model substrates. Moreover, both RNF5 and RNF185 play important roles in cell adhesion and migration through the modulation of cell migration by ubiquitinating paxillin. Arabidopsis thaliana RING membrane-anchor proteins (AtRMAs) are also included in this family. They possess E3 ubiquitin-protein ligase activity and may play a role in the growth and development of Arabidopsis. All members of this family contain a C3HC4-type RING-HC finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|..
gi 221044924 550 ICAICYQDMKSAVITPCSHFFHAGCLKKWL---YVQETCPLC 588
Cdd:cd16534    2 ECNICLDTASDPVVTMCGHLFCWPCLYQWLetrPDRQTCPVC 43

RING finger, H2 subclass, found in RING finger protein 13 (RNF13) and similar proteins; RNF13 is a widely expressed membrane-associated E3 ubiquitin-protein ligase that is functionally significant in the regulation of cancer development, muscle cell growth, and neuronal development. Its expression is developmentally regulated during myogenesis and is upregulated in various tumors. RNF13 negatively regulates cell proliferation through its E3 ligase activity. It functions as an important regulator of inositol-requiring transmembrane kinase/endonuclease IRE1alpha, mediating endoplasmic reticulum (ER) stress-induced apoptosis through the activation of the IRE1alpha-TRAF2-JNK signaling pathway. Moreover, RNF13 is involved in the regulation of the soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE) complex via the ubiquitination of snapin, a SNAP25-interacting protein, which thereby controls synaptic function. In addition, RNF13 participates in regulating the function of satellite cells by modulating cytokine composition. RNF13 is evolutionarily conserved among many metazoans and contains an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C-terminal C3H2C3-type RING-H2 finger domain followed by a putative PEST sequence.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....
gi 221044924 549 DICAIC---YQDMKSAVITPCSHFFHAGCLKKWLY-VQETCPLC 588
Cdd:cd16796    9 DVCAICldeYEEGDKLRILPCSHAYHCKCVDPWLTkTKKTCPVC 52

RING finger, H2 subclass, found in BRCA1-associated protein (BRAP2) and similar proteins; BRAP2, also known as impedes mitogenic signal propagation (IMP), RING finger protein 52, or renal carcinoma antigen NY-REN-63, is a novel cytoplasmic protein interacting with the two functional nuclear localization signal (NLS) motifs of BRCA1, a nuclear protein linked to breast cancer. It also binds to the SV40 large T antigen NLS motif and the bipartite NLS motif found in mitosin. BRAP2 serves as a cytoplasmic retention protein and plays a role in the regulation of nuclear protein transport. It contains an N-terminal RNA recognition motif (RRM), also known as RBD (RNA binding domain) or RNP (ribonucleoprotein domain), followed by a C3H2C3-type RING-H2 finger and a UBP-type zinc finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|..
gi 221044924 551 CAICYQDM----KSAVITPCSHFFHAGCLKKWLyvQETCPLC 588
Cdd:cd16457    3 CPVCLERMdesvSGILTILCNHSFHCSCLSKWG--DSSCPVC 42

RING finger, HC subclass, found in helicase-like transcription factor (HLTF) and similar proteins; HLTF, also known as DNA-binding protein/plasminogen activator inhibitor 1 regulator, HIP116, RING finger protein 80, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 3, or sucrose nonfermenting protein 2-like 3, is a yeast RAD5 homolog found in mammals. It has both E3 ubiquitin ligase and DNA helicase activities, and plays a pivotal role in the template-switching pathway of DNA damage tolerance. It is involved in Lys-63-linked poly-ubiquitination of proliferating cell nuclear antigen (PCNA) at Lys-164 and in the regulation of DNA damage tolerance. It shows double-stranded DNA translocase activity with 3'-5' polarity, thereby facilitating regression of the replication fork. HLTF contains an N-terminal HIRAN (HIP116 and RAD5 N-terminal) domain, a SWI/SNF helicase domain that is divided into N- and C-terminal parts by an insertion of a C3HC4-type RING-HC finger involved in the poly-ubiquitination of PCNA.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*...
gi 221044924 551 CAICYQDMKSAVITPCSHFFHAGCLKKWLYV-QETCPLCHCHLKNSSQ 597
Cdd:cd16509    6 CAICLDSLTNPVITPCAHVFCRRCICEVIQReKAKCPMCRAPLSASDL 53

RING finger, HC subclass, found in topoisomerase I-binding arginine/serine-rich protein (Topors) and similar proteins; Topors, also known as topoisomerase I-binding RING finger protein, tumor suppressor p53- binding protein 3, or p53-binding protein 3 (p53BP3), is a ubiquitously expressed nuclear E3 ubiquitin-protein ligase that can ligate both ubiquitin and small ubiquitin-like modifier (SUMO) to substrate proteins in the nucleus. It contains an N-terminal C3HC4-type RING-HC finger which ligates ubiquitin to its target proteins including DNA topoisomerase I, p53, NKX3.1, H2AX, and the AAV-2 Rep78/68 proteins. As a RING-dependent E3 ubiquitin ligase, Topors works with the E2 enzymes UbcH5a, UbcH5c, and UbcH6, but not with UbcH7, CDC34, or UbcH2b. Topors acts as a tumor suppressor in various malignancies. It regulates p53 modification, suggesting it may be responsible for astrocyte elevated gene-1 (AEG-1, also known as metadherin, or LYRIC) ubiquitin modification. Plk1-mediated phosphorylation of Topors inhibits Topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation. It also functions as a negative regulator of the prostate tumor suppressor NKX3.1. Moreover, Topors is associated with promyelocytic leukemia nuclear bodies, and may be involved in the cellular response to camptothecin. It also plays a key role in the turnover of H2AX protein, discriminating the type of DNA damaging stress. Furthermore, Topors is a cilia-centrosomal protein associated with autosomal dominant retinal degeneration. Mutations in TOPORS cause autosomal dominant retinitis pigmentosa (adRP).

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|..
gi 221044924 549 DICAICYQDMKS--AVITPCSHFFHAGCLKKWLYVQETCPLC 588
Cdd:cd16574    2 SSCPICLDRFENekAFLDGCFHAFCFTCILEWSKVKNECPLC 43

RING finger, H2 subclass, found in RING finger proteins RNF43, ZNRF3, and similar proteins; RNF43 and ZNRF3 (also known as RNF203) are transmembrane E3 ubiquitin-protein ligases that belong to the PA-TM-RING ubiquitin ligase family, characterized by containing an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C3H2C3-type RING-H2 finger followed by a long C-terminal region. Both RNF43 and RNF203 function as tumor suppressors involved in the regulation of Wnt/beta-catenin signaling. They negatively regulate Wnt signaling by interacting with complexes of frizzled (FZD) receptors and low-density lipoprotein receptor-related protein (LRP) 5/6, which leads to ubiquitination of FZD and endocytosis of the Wnt receptor. Dishevelled (DVL), a positive Wnt regulator, is required for ZNRF3/RNF43-mediated ubiquitination and degradation of FZD. They also associate with R-spondin 1 (RSPO1). This interaction may block FZD ubiquitination and enhances Wnt signaling.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|.
gi 221044924 551 CAIC---YQDMKSAVITPCSHFFHAGCLKKWLYVQETCPLC 588
Cdd:cd16666    2 CAICleeYEEGQELRVLPCQHEFHRKCVDPWLLQNHTCPLC 42

RING finger, H2 subclass, found in RING finger protein 103 (RNF103) and similar proteins; RNF103, also known as KF-1 or zinc finger protein 103 homolog (Zfp-103), is an endoplasmic reticulum (ER)-resident E3 ubiquitin-protein ligase that is widely expressed in many different organs, including brain, heart, kidney, spleen, and lung. It is involved in the ER-associated degradation (ERAD) pathway by interacting with components of the ERAD pathway, including Derlin-1 and VCP. RNF103 contains several hydrophobic regions at its N-terminal and middle regions, as well as a C-terminal C3H2C3-type RING-H2 finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|..
gi 221044924 551 CAICYQDMKSAVIT---PCSHFFHAGCLKKWLY-VQETCPLC 588
Cdd:cd16473    7 CAICLENYQNGDLLrglPCGHVFHQNCIDVWLErDNHCCPVC 48

RING finger, H2 subclass, found in RING finger protein 38 (RNF38) and similar proteins; RNF38 is a nuclear E3 ubiquitin protein ligase that is widely expressed throughout the human body, and is especially highly expressed in the heart, brain, placenta and the testis. It recognizes p53 as a substrate for ubiquitination, and thus plays a role in regulating p53. The overexpression of RNF38 increases p53 ubiquitination and alters p53 localization. It is also capable of autoubiquitination. RNF38 expression is negatively regulated by the serotonergic system. Induction of RNF38 may be involved in the anxiety-like behavior or non-cell autonomy in Oryzias latipes by the decline of serotonin (5-HT) levels. RNF38 contains a coiled-coil motif, a KIL motif (Lys-X2-Ile/Leu-X2-Ile/Leu, X can be any amino acid), a C3H2C3-type RING-H2 finger, as well as two potential nuclear localization signals.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*..
gi 221044924 545 EKHNDICAICYQDMKSAV---ITPCSHFFHAGCLKKWLYVQETCPLC 588
Cdd:cd16679   17 QSEQTLCVVCMCDFESRQllrVLPCNHEFHAKCVDKWLKANRTCPIC 63

RING finger, HC subclass, found in Arabidopsis thaliana protein BREAST CANCER SUSCEPTIBILITY 1 homolog (AtBRCA1) and similar proteins; AtBRCA1 plays a role in DNA repair and in cell-cycle control. It is required for the repair of DNA double-strand breaks (DSBs), both natural and induced by genotoxic stress, by homologous recombination (HR). AtBRCA1 contains a typical C3HC4-type RING-HC finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|.
gi 221044924 551 CAICYQDMKSAVITPCSHFFHAGCLKKWLYVQETCPLCHCH 591
Cdd:cd23147    7 CPICLSLFKSAANLSCNHCFCAGCIGESLKLSAICPVCKIP 47

RING finger, HC subclass, found in E3 ubiquitin-protein ligase Cbl-c and similar proteins; Cbl-c, also known as RING finger protein 57 (RNF57), SH3-binding protein Cbl-3, SH3-binding protein Cbl-c, or signal transduction protein Cbl-c, is an E3 ubiquitin-protein ligase expressed exclusively in epithelial cells. It contains a tyrosine-kinase-binding domain (TKB, also known as the phosphotyrosine binding PTB domain, composed of a four helix-bundle, a Ca2+ binding EF-hand and a highly variant SH2 domain), a C3HC4-type RING-HC finger, and a short proline-rich region, but lacks the ubiquitin-associated (UBA) leucine zipper motif that are present in Cbl and Cbl-b. Cbl-c acts as a regulator of epidermal growth factor receptor (EGFR)-mediated signal transduction. It also suppresses v-Src-induced transformation through ubiquitin-dependent protein degradation. Moreover, Cbl-c ubiquitinates and downregulates RETMEN2A and implicates Enigma (PDLIM7) as a positive regulator of RETMEN2A by blocking Cbl-mediated ubiquitination and degradation. The ubiquitin ligase activity of Cbl-c is increased via the interaction of its RING-HC finger domain with a LIM domain of the paxillin homolog, hydrogen peroxide induced construct 5 (Hic-5).

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*.
gi 221044924 549 DICAICYQDMKSAVITPCSHFFHAGCLKKWLYV-QETCPLCHCHLK 593
Cdd:cd16710   14 ELCKICAERDKDVRIEPCGHLLCSCCLAAWQHSdSQTCPFCRCEIK 59

RING finger, H2 subclass, found in RING finger protein 149 (RNF149) and similar proteins; RNF149, also known as DNA polymerase-transactivated protein 2, is an E3 ubiquitin-protein ligase that interacts with wild-type v-Raf murine sarcoma viral oncogene homolog B1 (BRAF), a RING domain-containing E3 ubiquitin ligase involved in control of gene transcription, translation, cytoskeletal organization, cell adhesion, and epithelial development. RNF149 induces the ubiquitination of wild-type BRAF and promotes its proteasome-dependent degradation. Mutated RNF149 has been found in some human breast, ovarian, and colorectal cancers. RNF149 contains an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C-terminal C3H2C3-type RING-H2 finger domain followed by a putative PEST sequence.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|.
gi 221044924 551 CAICYQDMKS---AVITPCSHFFHAGCLKKWLYVQETCPLC 588
Cdd:cd16804    2 CAVCIENYKSkdvVRILPCKHVFHRICIDPWLLEHRTCPMC 42

RING finger, H2 subclass, found in Arabidopsis thaliana NEP1-interacting protein-like 1 (NIPL1) and similar proteins; This subfamily includes Arabidopsis thaliana NIPL1 and MISFOLDED PROTEIN SENSING RING E3 LIGASE 1 (MPSR1). NIPL1, also called RING-H2 finger protein ATL27, may be involved in the early steps of the plant defense signaling pathway. MPSR1 is a cytoplasmic E3 ubiquitin-protein ligase involved in protein quality control (PQC) under proteotoxic stress. It is essential for plant survival under proteotoxic stress. It functions by removing damaged proteins before they form cytotoxic aggregates. It recognizes misfolded proteins selectively and tethers polyubiquitin chains to the proteins directly for subsequent degradation by the 26S proteasome pathway. Members of this subfamily contain a C3H2C3-type RING-H2 finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|..
gi 221044924 551 CAICYQDMKSAVIT----PCSHFFHAGCLKKWLYVQETCPLC 588
Cdd:cd23119    2 CTICLQDLQVGEIArslpHCHHTFHLGCVDKWLGRHGSCPVC 43

RING finger, H2 subclass, found in RING finger protein 126 (RNF126) and similar proteins; RNF126 is a Bag6-dependent E3 ubiquitin ligase that is involved in the mislocalized protein (MLP) pathway of quality control. It regulates the retrograde sorting of the cation-independent mannose 6-phosphate receptor (CI-MPR). Moreover, RNF126 promotes cancer cell proliferation by targeting the tumor suppressor p21 for ubiquitin-mediated degradation, and could be a novel therapeutic target in breast and prostate cancers. It is also able to ubiquitylate cytidine deaminase (AID), a poorly soluble protein that is essential for antibody diversification. In addition, RNF126 and the related protein, RNF115 associate with the epidermal growth factor receptor (EGFR) and promote ubiquitylation of EGFR, suggesting they play a role in the ubiquitin-dependent sorting and downregulation of membrane receptors. RNF126 contains an N-terminal BCA2 Zinc-finger domain (BZF), the AKT-phosphorylation sites, and the C-terminal C3H2C3-type RING-H2 finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|.
gi 221044924 551 CAICYQDM---KSAVITPCSHFFHAGCLKKWLYVQETCPLC 588
Cdd:cd16801    2 CPVCKEDYtvgENVRQLPCNHLFHNDCIVPWLEQHDTCPVC 42

Modified RING finger, HC subclass (C3HC3D-type), found in ligand of Numb protein LNX1, LNX2, and similar proteins; The ligand of Numb protein X (LNX) family, also known as PDZ and RING (PDZRN) family, includes LNX1-5, which can interact with Numb, a key regulator of neurogenesis and neuronal differentiation. LNX5 (also known as PDZK4 or PDZRN4L) shows high sequence homology to LNX3 and LNX4, but it lacks the RING domain. LNX1-4 proteins function as E3 ubiquitin ligases and have a unique domain architecture consisting of an N-terminal RING-HC finger for E3 ubiquitin ligase activity and either two or four PDZ domains necessary for substrate-binding. LNX1/LNX2-like proteins contain a modified C3HC3D-type RING-HC finger and four PDZ domains. This model corresponds to the RING finger.

                         10        20        30
                 ....*....|....*....|....*....|....*...
gi 221044924 550 ICAICYQDMKSAVITPCSHFFHAGCLKKWLYVQETCPL 587
Cdd:cd16637    3 TCHICLQPLVEPLDTPCGHTFCYKCLTNYLKIQQCCPL 40

RING finger, H2 subclass, found in RING finger proteins, RNF130, RNF149, RNF150 and similar proteins; This subfamily includes RING finger proteins, RNF130, RNF149 and RNF150, which belong to a larger PA-TM-RING ubiquitin ligase family that has been characterized by an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C-terminal C3H2C3-type RING-H2 finger domain followed by a putative PEST sequence. RNF130, also known as Goliath homolog (H-Goliath), is a paralog of RNF128. It is a transmembrane E3 ubiquitin-protein ligase expressed in leukocytes. It has a self-ubiquitination property and controls the development of T cell clonal anergy by ubiquitination. RNF133 is a testis-specific endoplasmic reticulum-associated E3 ubiquitin ligase that may play a role in sperm maturation through an ER-associated degradation (ERAD) pathway. RNF149, also known as DNA polymerase-transactivated protein 2, is an E3 ubiquitin-protein ligase that induces the ubiquitination of wild-type v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) and promotes its proteasome-dependent degradation. RNF150 polymorphisms may be associated with chronic obstructive pulmonary disease (COPD) risk in the Chinese population. This subfamily also includes Drosophila melanogaster protein goliath (d-goliath), also known as protein g1, which is one of the founding members of the group. It was originally identified as a transcription factor involved in the embryo mesoderm formation.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|.
gi 221044924 551 CAIC---YQDMKSAVITPCSHFFHAGCLKKWLYVQETCPLC 588
Cdd:cd16668    2 CAVCiepYKPSDVIRILPCKHIFHKSCVDPWLLEHRTCPMC 42

RING finger, HC subclass, found in ligand of numb protein X 3 (LNX3); LNX3, also known as PDZ domain-containing RING finger protein 3 (PDZRN3), or Semaphorin cytoplasmic domain-associated protein 3 (SEMACAP3), is an E3 ubiquitin-protein ligase that was first identified as a Semaphorin-binding partner. It is also responsible for the ubiquitination and degradation of Numb, a component of the Notch signaling pathway that functions in the specification of cell fates during development and is known to control cell numbers during neurogenesis in vertebrates. LNX3 acts as a negative regulator of osteoblast differentiation by inhibiting Wnt-beta-catenin signaling. LNX3 also plays an important role in neuromuscular junction formation. It interacts with and ubiquitinates the muscle specific tyrosine kinase (MuSK), thus promoting its endocytosis and negatively regulating the cell surface expression of this key regulator of postsynaptic assembly. LNX3 contains an N-terminal C3HC4-type RING-HC finger, two PDZ domains, and a C-terminal LNX3 homology (LNX3H) domain.

                         10        20        30
                 ....*....|....*....|....*....|....*..
gi 221044924 551 CAICYQDMKSAVITPCSHFFHAGCLKKWLYVQETCPL 587
Cdd:cd16718    7 CNLCNKVLEDPLTTPCGHVFCAGCVLPWVVQQGSCPV 43

RING finger, H2 subclass, found in RING finger protein 150 (RNF150) and similar proteins; RNF150 is a RING finger protein and its polymorphisms may be associated with chronic obstructive pulmonary disease (COPD) risk in the Chinese population. Further studies with larger numbers of participants worldwide are needed for validation of the relationships between RNF150 genetic variants and the pathogenesis of COPD. RNF150 contains an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C-terminal C3H2C3-type RING-H2 finger domain followed by a putative PEST sequence.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 221044924 543 QLEKHNDICAICYQDMKS---AVITPCSHFFHAGCLKKWLYVQETCPLC 588
Cdd:cd16805    1 ETESDFDNCAVCIEGYKPndvVRILPCRHLFHKSCVDPWLLDHRTCPMC 49

RING finger, HC subclass, found in ligand of numb protein X 4 (LNX4); LNX4, also known as PDZ domain-containing RING finger protein 4 (PDZRN4), or SEMACAP3-like protein (SEMCAP3L), is an E3 ubiquitin-protein ligase responsible for the ubiquitination and degradation of Numb, a component of the Notch signaling pathway that functions in the specification of cell fates during development and is known to control cell numbers during neurogenesis in vertebrates. LNX4 contains an N-terminal C3HC4-type RING-HC finger, two PDZ domains, and a C-terminal LNX3 homology (LNX3H) domain.

                         10        20        30
                 ....*....|....*....|....*....|....*..
gi 221044924 551 CAICYQDMKSAVITPCSHFFHAGCLKKWLYVQETCPL 587
Cdd:cd16719    7 CKLCGKVLEEPLSTPCGHVFCAGCLLPWAVQRRLCPL 43