Arl2-like protein 1 (Arl2l1) and Arl13; Arl2l1 (Arl2-like protein 1) and Arl13 form a subfamily of the Arf family of small GTPases. Arl2l1 was identified in human cells during a search for the gene(s) responsible for Bardet-Biedl syndrome (BBS). Like Arl6, the identified BBS gene, Arl2l1 is proposed to have cilia-specific functions. Arl13 is found on the X chromosome, but its expression has not been confirmed; it may be a pseudogene.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578807142  29 EYPEDVAPTVGFSKINLRQGKFEVTIFDLGGGIRIRGIWKNYYAESYGVIFVVDSSDEERMEETKEAMSEMLRHPRISGK 108
Cdd:cd04161   22 EIPKKVAPTVGFTPTKLRLDKYEVCIFDLGGGANFRGIWVNYYAEAHGLVFVVDSSDDDRVQEVKEILRELLQHPRVSGK 101

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 578807142 109 PILVLANKQDKEGALGEADVIECLSLEKLVNEHKCLCQIEPCSAISGYGKKIDKSIKKGLYWLLHV 174
Cdd:cd04161  102 PILVLANKQDKKNALLGADVIEYLSLEKLVNENKSLCHIEPCSAIEGLGKKIDPSIVEGLRWLLAA 167

Arl2-like protein 1 (Arl2l1) and Arl13; Arl2l1 (Arl2-like protein 1) and Arl13 form a subfamily of the Arf family of small GTPases. Arl2l1 was identified in human cells during a search for the gene(s) responsible for Bardet-Biedl syndrome (BBS). Like Arl6, the identified BBS gene, Arl2l1 is proposed to have cilia-specific functions. Arl13 is found on the X chromosome, but its expression has not been confirmed; it may be a pseudogene.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578807142  29 EYPEDVAPTVGFSKINLRQGKFEVTIFDLGGGIRIRGIWKNYYAESYGVIFVVDSSDEERMEETKEAMSEMLRHPRISGK 108
Cdd:cd04161   22 EIPKKVAPTVGFTPTKLRLDKYEVCIFDLGGGANFRGIWVNYYAEAHGLVFVVDSSDDDRVQEVKEILRELLQHPRVSGK 101

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 578807142 109 PILVLANKQDKEGALGEADVIECLSLEKLVNEHKCLCQIEPCSAISGYGKKIDKSIKKGLYWLLHV 174
Cdd:cd04161  102 PILVLANKQDKKNALLGADVIEYLSLEKLVNENKSLCHIEPCSAIEGLGKKIDPSIVEGLRWLLAA 167

ARF-like small GTPases; ARF, ADP-ribosylation factor; Ras homologues involved in vesicular transport. Activator of phospholipase D isoforms. Unlike Ras proteins they lack cysteine residues at their C-termini and therefore are unlikely to be prenylated. ARFs are N-terminally myristoylated. Contains ATP/GTP-binding motif (P-loop).

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578807142    36 PTVGFSKINLRQGKFEVTIFDLGGGIRIRGIWKNYYAESYGVIFVVDSSDEERMEETKEAMSEMLRHPRISGKPILVLAN 115
Cdd:smart00177  43 PTIGFNVETVTYKNISFTVWDVGGQDKIRPLWRHYYTNTQGLIFVVDSNDRDRIDEAREELHRMLNEDELRDAVILVFAN 122

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 578807142   116 KQDKEGALGEADVIECLSLEKLVNEHkclCQIEPCSAISGYGkkidksIKKGLYWL 171
Cdd:smart00177 123 KQDLPDAMKAAEITEKLGLHSIRDRN---WYIQPTCATSGDG------LYEGLTWL 169

small GTP-binding protein domain; Proteins with a small GTP-binding domain recognized by this model include Ras, RhoA, Rab11, translation elongation factor G, translation initiation factor IF-2, tetratcycline resistance protein TetM, CDC42, Era, ADP-ribosylation factors, tdhF, and many others. In some proteins the domain occurs more than once.This model recognizes a large number of small GTP-binding proteins and related domains in larger proteins. Note that the alpha chains of heterotrimeric G proteins are larger proteins in which the NKXD motif is separated from the GxxxxGK[ST] motif (P-loop) by a long insert and are not easily detected by this model. [Unknown function, General]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578807142   36 PTVGFS----KINLRQGKFEVTIFDLGGGIRIRGIWKNYYAESYGVIFVVD-SSDEERMEETKEAMSEMLRHPRISGKPI 110
Cdd:TIGR00231  33 PGTTRNyvttVIEEDGKTYKFNLLDTAGQEDYDAIRRLYYPQVERSLRVFDiVILVLDVEEILEKQTKEIIHHADSGVPI 112

                          90
                  ....*....|..
gi 578807142  111 LVLANKQDKEGA 122
Cdd:TIGR00231 113 ILVGNKIDLKDA 124

F0F1 ATP synthase subunit B; Validated

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 578807142 175 IARDFDALNERIQKETTEQRALEEQEKQERAERVRKlreeRKQNEQEQAEL 225
Cdd:PRK09173  27 IARSLDARADRIKNELAEARRLREEAQQLLAEYQRK----RKEAEKEAADI 73

Arl2-like protein 1 (Arl2l1) and Arl13; Arl2l1 (Arl2-like protein 1) and Arl13 form a subfamily of the Arf family of small GTPases. Arl2l1 was identified in human cells during a search for the gene(s) responsible for Bardet-Biedl syndrome (BBS). Like Arl6, the identified BBS gene, Arl2l1 is proposed to have cilia-specific functions. Arl13 is found on the X chromosome, but its expression has not been confirmed; it may be a pseudogene.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578807142  29 EYPEDVAPTVGFSKINLRQGKFEVTIFDLGGGIRIRGIWKNYYAESYGVIFVVDSSDEERMEETKEAMSEMLRHPRISGK 108
Cdd:cd04161   22 EIPKKVAPTVGFTPTKLRLDKYEVCIFDLGGGANFRGIWVNYYAEAHGLVFVVDSSDDDRVQEVKEILRELLQHPRVSGK 101

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 578807142 109 PILVLANKQDKEGALGEADVIECLSLEKLVNEHKCLCQIEPCSAISGYGKKIDKSIKKGLYWLLHV 174
Cdd:cd04161  102 PILVLANKQDKKNALLGADVIEYLSLEKLVNENKSLCHIEPCSAIEGLGKKIDPSIVEGLRWLLAA 167

Arf-related protein 1 (Arfrp1); Arfrp1 (Arf-related protein 1), formerly known as ARP, is a membrane-associated Arf family member that lacks the N-terminal myristoylation motif. Arfrp1 is mainly associated with the trans-Golgi compartment and the trans-Golgi network, where it regulates the targeting of Arl1 and the GRIP domain-containing proteins, golgin-97 and golgin-245, onto Golgi membranes. It is also involved in the anterograde transport of the vesicular stomatitis virus G protein from the Golgi to the plasma membrane, and in the retrograde transport of TGN38 and Shiga toxin from endosomes to the trans-Golgi network. Arfrp1 also inhibits Arf/Sec7-dependent activation of phospholipase D. Deletion of Arfrp1 in mice causes embryonic lethality at the gastrulation stage and apoptosis of mesodermal cells, indicating its importance in development.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578807142  31 PEDVAPTVGFSKINLRQGKFEVTIFDLGGGIRIRGIWKNYYAESYGVIFVVDSSDEERMEETKEAMSEMLRHPRISGKPI 110
Cdd:cd04160   32 PSKITPTVGLNIGTIEVGKARLMFWDLGGQEELRSLWDKYYAESHGVIYVIDSTDRERFNESKSAFEKVINNEALEGVPL 111

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 578807142 111 LVLANKQDKEGALGEADVIECLSLeKLVNEHKCLCQIEPCSAISGYGkkidksIKKGLYWL 171
Cdd:cd04160  112 LVLANKQDLPDALSVAEIKEVFDD-CIALIGRRDCLVQPVSALEGEG------VEEGIEWL 165

Arf-like 6 (Arl6) GTPase; Arl6 (Arf-like 6) forms a subfamily of the Arf family of small GTPases. Arl6 expression is limited to the brain and kidney in adult mice, but it is expressed in the neural plate and somites during embryogenesis, suggesting a possible role for Arl6 in early development. Arl6 is also believed to have a role in cilia or flagella function. Several proteins have been identified that bind Arl6, including Arl6 interacting protein (Arl6ip), and SEC61beta, a subunit of the heterotrimeric conducting channel SEC61p. Based on Arl6 binding to these effectors, Arl6 is also proposed to play a role in protein transport, membrane trafficking, or cell signaling during hematopoietic maturation. At least three specific homozygous Arl6 mutations in humans have been found to cause Bardet-Biedl syndrome, a disorder characterized by obesity, retinopathy, polydactyly, renal and cardiac malformations, learning disabilities, and hypogenitalism. Older literature suggests that Arl6 is a part of the Arl4/Arl7 subfamily, but analyses based on more recent sequence data place Arl6 in its own subfamily.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578807142  32 EDVAPTVGFSKINLRQGKFEVTIFDLGGGIRIRGIWKNYYAESYGVIFVVDSSDEERMEETKEAMSEMLRHPRISGK--P 109
Cdd:cd04157   27 QNIVPTVGFNVESFKKGNLSFTAFDMSGQGKYRGLWEHYYKNIQGIIFVIDSSDRLRMVVAKDELELLLNHPDIKHRriP 106

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 578807142 110 ILVLANKQDKEGALGEADVIECLSLEklvNEHKCLCQIEPCSAISGYGkkidksIKKGLYWL 171
Cdd:cd04157  107 ILFYANKMDLPDALTAVKITQLLCLE---NIKDKPWHIFASSALTGEG------LDEGVDWL 159

Arf-like 3 (Arl3) GTPase; Arl3 (Arf-like 3) is an Arf family protein that differs from most Arf family members in the N-terminal extension. In is inactive, GDP-bound form, the N-terminal extension forms an elongated loop that is hydrophobically anchored into the membrane surface; however, it has been proposed that this region might form a helix in the GTP-bound form. The delta subunit of the rod-specific cyclic GMP phosphodiesterase type 6 (PDEdelta) is an Arl3 effector. Arl3 binds microtubules in a regulated manner to alter specific aspects of cytokinesis via interactions with retinitis pigmentosa 2 (RP2). It has been proposed that RP2 functions in concert with Arl3 to link the cell membrane and the cytoskeleton in photoreceptors as part of the cell signaling or vesicular transport machinery. In mice, the absence of Arl3 is associated with abnormal epithelial cell proliferation and cyst formation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578807142  33 DVAPTVGFSKINLRQGKFEVTIFDLGGGIRIRGIWKNYYAESYGVIFVVDSSDEERMEETKEAMSEMLRHPRISGKPILV 112
Cdd:cd04155   42 HITPTQGFNIKNVQADGFKLNVWDIGGQRKIRPYWRNYFENTDVLIYVIDSADRKRFEEAGQELVELLEEEKLAGVPVLV 121

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 578807142 113 LANKQDKEGALGEADVIECLSLEKLVNEhkcLCQIEPCSAISGYGkkidksIKKGLYWL 171
Cdd:cd04155  122 FANKQDLLTAAPAEEVAEALNLHDIRDR---SWHIQACSAKTGEG------LQEGMNWV 171

Arf-like tumor suppressor gene 1 (ARLTS1 or Arl11); ARLTS1 (Arf-like tumor suppressor gene 1), also known as Arl11, is a member of the Arf family of small GTPases that is believed to play a major role in apoptotic signaling. ARLTS1 is widely expressed and functions as a tumor suppressor gene in several human cancers. ARLTS1 is a low-penetrance suppressor that accounts for a small percentage of familial melanoma or familial chronic lymphocytic leukemia (CLL). ARLTS1 inactivation seems to occur most frequently through biallelic down-regulation by hypermethylation of the promoter. In breast cancer, ARLTS1 alterations were typically a combination of a hypomorphic polymorphism plus loss of heterozygosity. In a case of thyroid adenoma, ARLTS1 alterations were polymorphism plus promoter hypermethylation. The nonsense polymorphism Trp149Stop occurs with significantly greater frequency in familial cancer cases than in sporadic cancer cases, and the Cys148Arg polymorphism is associated with an increase in high-risk familial breast cancer.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578807142  36 PTVGFSKINLR-QGKFEVTIFDLGGGIRIRGIWKNYYAESYGVIFVVDSSDEERMEETKEAMSEMLRHPRISGKPILVLA 114
Cdd:cd04156   29 PTVGFNVEMLQlEKHLSLTVWDVGGQEKMRTVWKCYLENTDGLVYVVDSSDEARLDESQKELKHILKNEHIKGVPVVLLA 108

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 578807142 115 NKQDKEGALGEADVIECLSLEKLVNEHKclCQIEPCSAISGYG 157
Cdd:cd04156  109 NKQDLPGALTAEEITRRFKLKKYCSDRD--WYVQPCSAVTGEG 149

Sar1 is an essential component of COPII vesicle coats; Sar1 is an essential component of COPII vesicle coats involved in export of cargo from the ER. The GTPase activity of Sar1 functions as a molecular switch to control protein-protein and protein-lipid interactions that direct vesicle budding from the ER. Activation of the GDP to the GTP-bound form of Sar1 involves the membrane-associated guanine nucleotide exchange factor (GEF) Sec12. Sar1 is unlike all Ras superfamily GTPases that use either myristoyl or prenyl groups to direct membrane association and function, in that Sar1 lacks such modification. Instead, Sar1 contains a unique nine-amino-acid N-terminal extension. This extension contains an evolutionarily conserved cluster of bulky hydrophobic amino acids, referred to as the Sar1-N-terminal activation recruitment (STAR) motif. The STAR motif mediates the recruitment of Sar1 to ER membranes and facilitates its interaction with mammalian Sec12 GEF leading to activation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578807142  36 PTVGFSKINLRQGKFEVTIFDLGGGIRIRGIWKNYYAESYGVIFVVDSSDEERMEETKEAMSEMLRHPRISGKPILVLAN 115
Cdd:cd00879   49 PTLHPTSEELTIGNVKFTTFDLGGHEQARRVWKDYFPEVDGIVFLVDAADPERFQESKEELDSLLNDEELANVPILILGN 128

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 578807142 116 KQDKEGALGEADVIECLSLEKLVNEHKCLCQIEP---------CSAISGYGkkidksIKKGLYWL 171
Cdd:cd00879  129 KIDKPGAVSEEELREALGLYGTTTGKGGVSLKVSnirpvevfmCSVVKRQG------YGEGFRWL 187

Arf-like 9 (Arl9) and 10 (Arl10) GTPases; Arl10-like subfamily. Arl9/Arl10 was identified from a human cancer-derived EST dataset. No functional information about the subfamily is available at the current time, but crystal structures of human Arl10b and Arl10c have been solved.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578807142  29 EYPEDVAPTVGFSKINLRQGKFEVTIFDLGGGIRIRGIWKNYYAESYGVIFVVDSSDEERMEETKEAMSEMLRHPRISGK 108
Cdd:cd04159   23 QFSEDTIPTVGFNMRKVTKGNVTIKVWDLGGQPRFRSMWERYCRGVNAIVYVVDAADREKLEVAKNELHDLLEKPSLEGI 102

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 578807142 109 PILVLANKQDKEGALGEADVIECLSLEKLVNEHKClcqiepCSAISGYGK-KIDKSIKkglyWLL 172
Cdd:cd04159  103 PLLVLGNKNDLPGALSVDELIEQMNLKSITDREVS------CYSISAKEKtNIDIVLD----WLI 157

ADP-ribosylation factor-1 (Arf1) and ADP-ribosylation factor-5 (Arf5); The Arf1-Arf5-like subfamily contains Arf1, Arf2, Arf3, Arf4, Arf5, and related proteins. Arfs1-5 are soluble proteins that are crucial for assembling coat proteins during vesicle formation. Each contains an N-terminal myristoylated amphipathic helix that is folded into the protein in the GDP-bound state. GDP/GTP exchange exposes the helix, which anchors to the membrane. Following GTP hydrolysis, the helix dissociates from the membrane and folds back into the protein. A general feature of Arf1-5 signaling may be the cooperation of two Arfs at the same site. Arfs1-5 are generally considered to be interchangeable in function and location, but some specific functions have been assigned. Arf1 localizes to the early/cis-Golgi, where it is activated by GBF1 and recruits the coat protein COPI. It also localizes to the trans-Golgi network (TGN), where it is activated by BIG1/BIG2 and recruits the AP1, AP3, AP4, and GGA proteins. Humans, but not rodents and other lower eukaryotes, lack Arf2. Human Arf3 shares 96% sequence identity with Arf1 and is believed to generally function interchangeably with Arf1. Human Arf4 in the activated (GTP-bound) state has been shown to interact with the cytoplasmic domain of epidermal growth factor receptor (EGFR) and mediate the EGF-dependent activation of phospholipase D2 (PLD2), leading to activation of the activator protein 1 (AP-1) transcription factor. Arf4 has also been shown to recognize the C-terminal sorting signal of rhodopsin and regulate its incorporation into specialized post-Golgi rhodopsin transport carriers (RTCs). There is some evidence that Arf5 functions at the early-Golgi and the trans-Golgi to affect Golgi-associated alpha-adaptin homology Arf-binding proteins (GGAs).

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578807142  36 PTVGFSKINLRQGKFEVTIFDLGGGIRIRGIWKNYYAESYGVIFVVDSSDEERMEETKEAMSEMLRHPRISGKPILVLAN 115
Cdd:cd04150   30 PTIGFNVETVEYKNISFTVWDVGGQDKIRPLWRHYFQNTQGLIFVVDSNDRERIGEAREELQRMLNEDELRDAVLLVFAN 109

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 578807142 116 KQDKEGALGEADVIECLSLEKLVNEHkclCQIEPCSAISGYGkkidksIKKGLYWL 171
Cdd:cd04150  110 KQDLPNAMSAAEVTDKLGLHSLRNRN---WYIQATCATSGDG------LYEGLDWL 156

ADP-ribosylation factor; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578807142  36 PTVGFSKINLRQGKFEVTIFDLGGGIRIRGIWKNYYAESYGVIFVVDSSDEERMEETKEAMSEMLRHPRISGKPILVLAN 115
Cdd:PTZ00133  47 PTIGFNVETVEYKNLKFTMWDVGGQDKLRPLWRHYYQNTNGLIFVVDSNDRERIGDAREELERMLSEDELRDAVLLVFAN 126

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 578807142 116 KQDKEGALGEADVIECLSLEKLVNEHkclCQIEPCSAISGYGkkidksIKKGLYWL 171
Cdd:PTZ00133 127 KQDLPNAMSTTEVTEKLGLHSVRQRN---WYIQGCCATTAQG------LYEGLDWL 173

Arf-like 4 (Arl4) and 7 (Arl7) GTPases; Arl4 (Arf-like 4) is highly expressed in testicular germ cells, and is found in the nucleus and nucleolus. In mice, Arl4 is developmentally expressed during embryogenesis, and a role in somite formation and central nervous system differentiation has been proposed. Arl7 has been identified as the only Arf/Arl protein to be induced by agonists of liver X-receptor and retinoid X-receptor and by cholesterol loading in human macrophages. Arl7 is proposed to play a role in transport between a perinuclear compartment and the plasma membrane, apparently linked to the ABCA1-mediated cholesterol secretion pathway. Older literature suggests that Arl6 is a part of the Arl4/Arl7 subfamily, but analyses based on more recent sequence data place Arl6 in its own subfamily.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578807142  29 EYPEDVaPTVGFS--KINLRQGKFEVTIF---DLGGGIRIRGIWKNYYAESYGVIFVVDSSDEERMEETKEAMSEMLRHP 103
Cdd:cd04152   27 EFVNTV-PTKGFNteKIKVSLGNAKGVTFhfwDVGGQEKLRPLWKSYTRCTDGIVFVVDSVDVERMEEAKTELHKITKFS 105

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 578807142 104 RISGKPILVLANKQDKEGALGEADVIECLSLEKLVNEhkCLCQIEPCSAISGYG 157
Cdd:cd04152  106 ENQGVPVLVLANKQDLPNALPVSEVEKLLALHELSSS--TPWHVQPACAIIGEG 157

Sar1p-like members of the Ras-family of small GTPases; Yeast SAR1 is an essential gene required for transport of secretory proteins from the endoplasmic reticulum to the Golgi apparatus.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578807142    36 PTVGFSKINLRQGKFEVTIFDLGGGIRIRGIWKNYYAESYGVIFVVDSSDEERMEETKEAMSEMLRHPRISGKPILVLAN 115
Cdd:smart00178  47 PTQHPTSEELAIGNIKFTTFDLGGHQQARRLWKDYFPEVNGIVYLVDAYDKERFAESKRELDALLSDEELATVPFLILGN 126

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 578807142   116 KQDKEGALGEADVIECLSLEKLVNEHKCLCQ----IEPCSAI--SGYGkkidksikKGLYWLLHVI 175
Cdd:smart00178 127 KIDAPYAASEDELRYALGLTNTTTGKGKVGVrpveVFMCSVVrrMGYG--------EGFKWLSQYI 184

Rat sarcoma (Ras)-like superfamily of small guanosine triphosphatases (GTPases); Ras-like GTPase superfamily. The Ras-like superfamily of small GTPases consists of several families with an extremely high degree of structural and functional similarity. The Ras superfamily is divided into at least four families in eukaryotes: the Ras, Rho, Rab, and Sar1/Arf families. This superfamily also includes proteins like the GTP translation factors, Era-like GTPases, and G-alpha chain of the heterotrimeric G proteins. Members of the Ras superfamily regulate a wide variety of cellular functions: the Ras family regulates gene expression, the Rho family regulates cytoskeletal reorganization and gene expression, the Rab and Sar1/Arf families regulate vesicle trafficking, and the Ran family regulates nucleocytoplasmic transport and microtubule organization. The GTP translation factor family regulates initiation, elongation, termination, and release in translation, and the Era-like GTPase family regulates cell division, sporulation, and DNA replication. Members of the Ras superfamily are identified by the GTP binding site, which is made up of five characteristic sequence motifs, and the switch I and switch II regions.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578807142  36 PTVGFSKINLR--QGKFEVTIFDLGGGIRIRGIWKNYYAESY-----GVIFVVDSSDEERMEETKEAMSEMLRHPrisGK 108
Cdd:cd00882   31 TTRDPDVYVKEldKGKVKLVLVDTPGLDEFGGLGREELARLLlrgadLILLVVDSTDRESEEDAKLLILRRLRKE---GI 107

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*....
gi 578807142 109 PILVLANKQDKegaLGEADVIECLSLEKLVNEHKclCQIEPCSAISGYG 157
Cdd:cd00882  108 PIILVGNKIDL---LEEREVEELLRLEELAKILG--VPVFEVSAKTGEG 151

Ras-related in brain (Rab) family of small guanosine triphosphatases (GTPases); Rab GTPases form the largest family within the Ras superfamily. There are at least 60 Rab genes in the human genome, and a number of Rab GTPases are conserved from yeast to humans. Rab GTPases are small, monomeric proteins that function as molecular switches to regulate vesicle trafficking pathways. The different Rab GTPases are localized to the cytosolic face of specific intracellular membranes, where they regulate distinct steps in membrane traffic pathways. In the GTP-bound form, Rab GTPases recruit specific sets of effector proteins onto membranes. Through their effectors, Rab GTPases regulate vesicle formation, actin- and tubulin-dependent vesicle movement, and membrane fusion. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which mask C-terminal lipid binding and promote cytosolic localization. While most unicellular organisms possess 5-20 Rab members, several have been found to possess 60 or more Rabs; for many of these Rab isoforms, homologous proteins are not found in other organisms. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Since crystal structures often lack C-terminal residues, the lipid modification site is not available for annotation in many of the CDs in the hierarchy, but is included where possible.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578807142  29 EYPEDVAPTVG---FSK-INLRQGKFEVTIFDLGGGIRIRGIWKNYYAESYGVIFVVDSSDEERMEETKEAMSEMLRH-- 102
Cdd:cd00154   24 KFSENYKSTIGvdfKSKtIEVDGKKVKLQIWDTAGQERFRSITSSYYRGAHGAILVYDVTNRESFENLDKWLNELKEYap 103

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 578807142 103 PRIsgkPILVLANKQDkegaLGEADVIECLSLEKLVNEHKCLCqIEpCSAISGYG 157
Cdd:cd00154  104 PNI---PIILVGNKSD----LEDERQVSTEEAQQFAKENGLLF-FE-TSAKTGEN 149

Signal recognition particle receptor, beta subunit (SR-beta), together with SR-alpha, forms the heterodimeric signal recognition particle (SRP); Signal recognition particle receptor, beta subunit (SR-beta). SR-beta and SR-alpha form the heterodimeric signal recognition particle (SRP or SR) receptor that binds SRP to regulate protein translocation across the ER membrane. Nascent polypeptide chains are synthesized with an N-terminal hydrophobic signal sequence that binds SRP54, a component of the SRP. SRP directs targeting of the ribosome-nascent chain complex (RNC) to the ER membrane via interaction with the SR, which is localized to the ER membrane. The RNC is then transferred to the protein-conducting channel, or translocon, which facilitates polypeptide translation across the ER membrane or integration into the ER membrane. SR-beta is found only in eukaryotes; it is believed to control the release of the signal sequence from SRP54 upon binding of the ribosome to the translocon. High expression of SR-beta has been observed in human colon cancer, suggesting it may play a role in the development of this type of cancer.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578807142  36 PTVGFSKINLRQGKFeVTIFDLGGGIRIR-GIWKNYYAESYGVIFVVDSSD-EERMEETKEAMSEML----RHPRisGKP 109
Cdd:cd04105   34 PNVASFYSNSSKGKK-LTLVDVPGHEKLRdKLLEYLKASLKAIVFVVDSATfQKNIRDVAEFLYDILtdleKIKN--KIP 110

                 ....*....
gi 578807142 110 ILVLANKQD 118
Cdd:cd04105  111 ILIACNKQD 119

GTP-binding protein Der; Reviewed

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 578807142  77 VIFVVDSSdeERMEETKEAMSEMLRHpriSGKPILVLANKQDkeGALGEADVIECLSL 134
Cdd:PRK03003 121 VLFVVDAT--VGATATDEAVARVLRR---SGKPVILAANKVD--DERGEADAAALWSL 171

Rab GTPase family J-like (RabJ-like); RJLs are found in many protists and as chimeras with C-terminal DNAJ domains in deuterostome metazoa. They are not found in plants, fungi, and protostome metazoa, suggesting a horizontal gene transfer between protists and deuterostome metazoa. RJLs lack any known membrane targeting signal and contain a degenerate phosphate/magnesium-binding 3 (PM3) motif, suggesting an impaired ability to hydrolyze GTP. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578807142  36 PTVGF----SKINLRQGKFEVTIFDLGGGIRIRGIWKNYYAESYGVIFVVDSSDEERMEE----TKEAMSEMLRHPRISG 107
Cdd:cd04119   31 PTIGIdygvKKVSVRNKEVRVNFFDLSGHPEYLEVRNEFYKDTQGVLLVYDVTDRQSFEAldswLKEMKQEGGPHGNMEN 110

                         90
                 ....*....|...
gi 578807142 108 KPILVLANKQDKE 120
Cdd:cd04119  111 IVVVVCANKIDLT 123

EngA1 GTPase contains the first domain of EngA; This EngA1 subfamily CD represents the first GTPase domain of EngA and its orthologs, which are composed of two adjacent GTPase domains. Since the sequences of the two domains are more similar to each other than to other GTPases, it is likely that an ancient gene duplication, rather than a fusion of evolutionarily distinct GTPases, gave rise to this family. Although the exact function of these proteins has not been elucidated, studies have revealed that the E. coli EngA homolog, Der, and Neisseria gonorrhoeae EngA are essential for cell viability. A recent report suggests that E. coli Der functions in ribosome assembly and stability.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578807142  77 VIFVVDSsDEERMEETKEaMSEMLRHpriSGKPILVLANKQDKEGALGEADVIECLSLEKLVnehkclcqiePCSAISGY 156
Cdd:cd01894   80 ILFVVDG-REGLTPADEE-IAKYLRK---SKKPVILVVNKIDNIKEEEEAAEFYSLGFGEPI----------PISAEHGR 144

                 .
gi 578807142 157 G 157
Cdd:cd01894  145 G 145

Rab subfamily of small GTPases; Rab GTPases are implicated in vesicle trafficking.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578807142    29 EYPEDVAPTVG--F-SK-INLRQGKFEVTIFDLGGGIRIRGIWKNYYAESYGVIFVVDSSDEERMEETKEAMSEMLRH-- 102
Cdd:smart00175  24 KFSEQYKSTIGvdFkTKtIEVDGKRVKLQIWDTAGQERFRSITSSYYRGAVGALLVYDITNRESFENLENWLKELREYas 103

                           90
                   ....*....|....*...
gi 578807142   103 PRIsgkPILVLANKQDKE 120
Cdd:smart00175 104 PNV---VIMLVGNKSDLE 118

F0F1 ATP synthase subunit B; Validated

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 578807142 175 IARDFDALNERIQKETTEQRALEEQEKQERAERVRKlreeRKQNEQEQAEL 225
Cdd:PRK09173  27 IARSLDARADRIKNELAEARRLREEAQQLLAEYQRK----RKEAEKEAADI 73

Double Era-like domain GTPase Der [Translation, ribosomal structure and biogenesis];

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 578807142  77 VIFVVD------SSDEErmeetkeaMSEMLRHpriSGKPILVLANKQDkeGALGEADVIECLSL 134
Cdd:COG1160   86 ILFVVDgragltPLDEE--------IAKLLRR---SGKPVILVVNKVD--GPKREADAAEFYSL 136