first ubiquitin-like (Ubl) domain located at the N-terminus of coronavirus SARS-CoV non-structural protein 3 (Nsp3) and related proteins; This ubiquitin-like (Ubl) domain (Ubl1) is found at the N-terminus of coronavirus Nsp3, a large multi-functional multi-domain protein which is an essential component of the replication/transcription complex (RTC). The functions of Ubl1 in CoVs are related to single-stranded RNA (ssRNA) binding and to interacting with the nucleocapsid (N) protein. SARS-CoV Ubl1 has been shown to bind ssRNA having AUA patterns, and since the 5'-UTR of the SARS-CoV genome has a number of AUA repeats, it may bind there. In mouse hepatitis virus (MHV), this Ubl1 domain binds the cognate N protein. Adjacent to Ubl1 is a Glu-rich acidic region (also referred to as hypervariable region, HVR); Ubl1 together with HVR has been called Nsp3a. Currently, the function of HVR in CoVs is unknown. This model corresponds to one of two Ubl domains in Nsp3; the other is located N-terminal to the papain-like protease (PLpro) and is not represented by this model.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034638728  91 NHETSIFIPAFESETKVRVNSNMRTEEVIKQLLQKFKIENSPQDFALHIIFATGEQRRLKKTDIPLLQRLLQGPSEKNAR 170
Cdd:cd17223     1 NYKTSVFTPAFGSETKVRINSNMTTQEVIKQLLQKFKIENSPNEFALYIIHATGEKKRLKNTDFPLWERLLQGPSGKIAK 80

                  ....*..
gi 1034638728 171 IFLMDKD 177
Cdd:cd17223    81 MFLMDKD 87

Ras-associating (RA) domain found in Ras-association domain-containing protein 6 (RASSF6); RASSF6 is a member of a family of six related classical RASSF1-6 proteins and is expressed as four transcripts via alternative splicing. All transcripts variant of RASSF6 contain the RA and SARAH domains. The RA domain of the classical RASSF protein family has the beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin. RA domains mediate interactions with Ras and other small GTPases, SARAH domains mediate protein-protein interactions crucial in the pathways that induce cell cycle arrest and apoptosis. RASSF6 is ubiquitiated and degraded by interacting with MDM2 to stabilize P53 and regulates apoptosis and cell cycle. RASSF6 is a tumor suppressor protein and is epigenetically silenced in childhood leukemia and neuroblastomas. Overexpression of RASSF6 causes apoptosis in HeLa cells.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034638728  91 NHETSIFIPAFESETKVRVNSNMRTEEVIKQLLQKFKIENSPQDFALHIIFATGEQRRLKKTDIPLLQRLLQGPSEKNAR 170
Cdd:cd17223     1 NYKTSVFTPAFGSETKVRINSNMTTQEVIKQLLQKFKIENSPNEFALYIIHATGEKKRLKNTDFPLWERLLQGPSGKIAK 80

                  ....*..
gi 1034638728 171 IFLMDKD 177
Cdd:cd17223    81 MFLMDKD 87

Ras association (RalGDS/AF-6) domain; RasGTP effectors (in cases of AF6, canoe and RalGDS); putative RasGTP effectors in other cases. Recent evidence (not yet in MEDLINE) shows that some RA domains do NOT bind RasGTP. Predicted structure similar to that determined, and that of the RasGTP-binding domain of Raf kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034638728  90 YNHETSIFIPAFESETK---VRVNSNMRTEEVIKQLLQKFKIENSPQDFAL-HIIFATGEQRRLKKTDIPLLQRLLQGPS 165
Cdd:pfam00788   1 DDGVLKVYTEDGKPGTTyktILVSSSTTAEEVIEALLEKFGLEDDPRDYVLvEVLERGGGERRLPDDECPLQIQLQWPRD 80

                          90
                  ....*....|...
gi 1034638728 166 EKNARIFLMDKDA 178
Cdd:pfam00788  81 ASDSRFLLRKRDD 93

Novel Ras effector 1 C-terminal SARAH (Sav/Rassf/Hpo) domain; The Nore1-SARAH, C-terminal, domain of Nore1, the tumour-suppressor, a novel Ras effector, has a characteriztic coiled-coil structure. It is a small helical module that is important in signal-transduction networks. The recombinant SARAH domain of Nore1 crystallizes as an anti-parallel homodimer with representative characteriztics of coiled coils. The central function of the SARAH domain seems to be the mediation of homo- and hetero-oligomerization between SARAH domain-containing proteins. Nore1 forms homo- and hetero complexes through its C-terminal SARAH (Sav/Rassf/Hpo) domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 1034638728 190 NFHFSLLESILQRLNEEEKREIQRIVTKFNKEKAIILKCL 229
Cdd:pfam16517   1 AFSLPELENFLRILDEEEEREIQQIRRKYTALRQKLQQAL 40

Ras-associating (RA) domain found in Ras-association domain-containing protein 6 (RASSF6); RASSF6 is a member of a family of six related classical RASSF1-6 proteins and is expressed as four transcripts via alternative splicing. All transcripts variant of RASSF6 contain the RA and SARAH domains. The RA domain of the classical RASSF protein family has the beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin. RA domains mediate interactions with Ras and other small GTPases, SARAH domains mediate protein-protein interactions crucial in the pathways that induce cell cycle arrest and apoptosis. RASSF6 is ubiquitiated and degraded by interacting with MDM2 to stabilize P53 and regulates apoptosis and cell cycle. RASSF6 is a tumor suppressor protein and is epigenetically silenced in childhood leukemia and neuroblastomas. Overexpression of RASSF6 causes apoptosis in HeLa cells.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034638728  91 NHETSIFIPAFESETKVRVNSNMRTEEVIKQLLQKFKIENSPQDFALHIIFATGEQRRLKKTDIPLLQRLLQGPSEKNAR 170
Cdd:cd17223     1 NYKTSVFTPAFGSETKVRINSNMTTQEVIKQLLQKFKIENSPNEFALYIIHATGEKKRLKNTDFPLWERLLQGPSGKIAK 80

                  ....*..
gi 1034638728 171 IFLMDKD 177
Cdd:cd17223    81 MFLMDKD 87

Ras-associating (RA) domain found in Ras-association domain-containing protein 2 (RASSF2); RASSF2 is a member of a family of six related classical RASSF1-6 proteins. The RASSF2 gene is transcribed into two major isoforms (A and C). RASSF2 is structurally related to RASSF1A but unlike RASSF1A It is primarily a nuclear protein. RASSF2 contains the RA and SARAH domains. The RA domain of the classical RASSF protein family has the beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin. RA domains mediate interactions with Ras and other small GTPases, and SARAH domains mediate protein-protein interactions crucial in the pathways that induce cell cycle arrest and apoptosis. RASSF2 is inactivated in different cancers and cancer cell lines by promoter methylation and loss of expression, implicating the correlation and significance of RASSF2 in tumorigenesis. In addition to regulating apoptosis and proliferation RASSF2 may have other functions as RASSF2 knockout mice develop normally for the first two weeks but then develop growth retardation and die 4 weeks after birth.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034638728  91 NHETSIFIPAFESETKVRVNSNMRTEEVIKQLLQKFKIENSPQDFALHIIFATGEQRRLKKTDIPLLQRLLQGPSEKNAR 170
Cdd:cd17221     1 NHKTSVFTPAYGSVTNVRINSTMTTPQVLKLLLNKFKIENSAEEFALYIVHTSGEKQKLKATDYPLIARILQGPCEQVSK 80

                  ....*..
gi 1034638728 171 IFLMDKD 177
Cdd:cd17221    81 VFLMEKD 87

C-terminal SARAH domain found in Ras-association domain-containing protein 6 (RASSF6); RASSF6 is one of six related proteins, the classical RASSF proteins (RASSF1-6), that contain a conserved RalGDS/AF6 Ras association (RA) domain located towards the C-terminus. It acts as a tumor suppressor protein involved in the induction of apoptosis, through both caspase-dependent and caspase-independent pathways. RASSF6 may function as a Ras effector protein. It is ubiquitinated and degraded by interacting with MDM2 to stabilize P53, and it regulates apoptosis and the cell cycle. RASSF6 is expressed as four transcripts via alternative splicing. All transcript variants of RASSF6 contain the RA and SARAH (Salvador-RassF-Hippo) domains. The RA domain of the classical RASSF proteins has the beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin. RA domains mediate interactions with Ras and other small GTPases. SARAH domains mediate protein-protein interactions crucial in the pathways that induce cell cycle arrest and apoptosis. This model corresponds to the SARAH domain of RASSF6.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 1034638728 187 QYINFHFSLLESILQRLNEEEKREIQRIVTKFNKEKAIILKCLQNK 232
Cdd:cd21895     1 QYINFELPFLESILQKLNEEEEREIQKIVAKYKKEKAILLQCLRSK 46

Ras association (RalGDS/AF-6) domain; RasGTP effectors (in cases of AF6, canoe and RalGDS); putative RasGTP effectors in other cases. Kalhammer et al. have shown that not all RA domains bind RasGTP. Predicted structure similar to that determined, and that of the RasGTP-binding domain of Raf kinase. Predicted RA domains in PLC210 and nore1 found to bind RasGTP. Included outliers (Grb7, Grb14, adenylyl cyclases etc.)

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034638728   88 HFYNHETSIFIPAFESETKVRVNSNMRTEEVIKQLLQKFKIENSPQDFALHIIFATGEQRRLKKTDIPLLQRLLQGPSEK 167
Cdd:smart00314   1 DTFVLRVYVDDLPGGTYKTLRVSSRTTARDVIQQLLEKFHLTDDPEEYVLVEVLPDGKERVLPDDENPLQLQKLWPRRGP 80

                           90
                   ....*....|
gi 1034638728  168 NARIFLMDKD 177
Cdd:smart00314  81 NLRFVLRKRD 90

Novel Ras effector 1 C-terminal SARAH (Sav/Rassf/Hpo) domain; The Nore1-SARAH, C-terminal, domain of Nore1, the tumour-suppressor, a novel Ras effector, has a characteriztic coiled-coil structure. It is a small helical module that is important in signal-transduction networks. The recombinant SARAH domain of Nore1 crystallizes as an anti-parallel homodimer with representative characteriztics of coiled coils. The central function of the SARAH domain seems to be the mediation of homo- and hetero-oligomerization between SARAH domain-containing proteins. Nore1 forms homo- and hetero complexes through its C-terminal SARAH (Sav/Rassf/Hpo) domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 1034638728 190 NFHFSLLESILQRLNEEEKREIQRIVTKFNKEKAIILKCL 229
Cdd:pfam16517   1 AFSLPELENFLRILDEEEEREIQQIRRKYTALRQKLQQAL 40

Ras-associating (RA) domain found in Ras-association domain family members, RASSF1, RASSF3, and RASSF5; The RASSF family of proteins shares a conserved RalGDS/AF6 Ras association (RA) domain which is located either at the C-terminus (RASSF1-6, the classical group) or at the N-terminus (RASSF7-10). RASSF1-6 contains a conserved SARAH (Salvador/RASSF/Hpo) motif adjacent to the RA domain that functions in scaffolding and regulatory interactions. The RA domain of the classical RASSF proteins has a beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin. Classical RASSF members interact either directly or indirectly with activated Ras. Ras proteins are small GTPases that are involved in cellular signal transduction. The classical RASSF proteins seem to modulate some of the growth inhibitory responses mediated by Ras and may serve as tumor suppressor genes. This family contains RASSF1, RASSF3, and RASSF5.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034638728  93 ETSIFIPAFESETkVRVNSNMRTEEVIKQLLQKFKIENSPQDFAL----HIIFATGEQRRLKKTDIPLLQRLLQGPSEKN 168
Cdd:cd01778    44 RTSFYLPKDTVKA-LHITSDTTAREVIEALLKKFKITDNPRKFALyertHEEEGKVKLRKLSDDERPLYLCLLWGSQGDS 122

                  ....*
gi 1034638728 169 ARIFL 173
Cdd:cd01778   123 KSFVL 127

Ras-associating (RA) domain 1 found in Afadin; Afadin, also termed ALL1-fused gene from chromosome 6 protein (AF-6), or canoe, is involved in many fundamental signaling cascades in cells. In addition, it is involved in oncogenesis and metastasis. Afadin has multiple domains: from the N-terminus to the C-terminus it has two Ras-associated (RA) domains, a forkhead-associated domain, a dilute domain, a PDZ domain, three proline-rich domains, and an F-actin-binding domain. RA domain-containing proteins function by interacting with Ras proteins directly or indirectly and are involved in several different functions ranging from tumor suppression to being oncoproteins. Ras proteins are small GTPases that are involved in cellular signal transduction. The RA domain has a beta-grasp ubiquitin-like (Ubl) fold with low sequence similarity to ubiquitin (Ub). Ub is a protein modifier in eukaryotes that is involved in various cellular processes including transcriptional regulation, cell cycle control, and DNA repair in eukaryotes. Afadin is abundant at cadherin-based adherens junctions in epithelial cells, endothelial cells, and fibroblasts. This family corresponds to the first RA domain of afadin, which mediates its self-association.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034638728 105 TK-VRVNSNMRTEEVIKQLLQKFKIEN---SPQDFALHIIFATGEQRRLKKTDIPLLQRL 160
Cdd:cd01782    37 TKcIRVSSTATTQDVIETLIEKFRPDMrmlSNPRYSLYEVHPNGEERKLDDDEKPLVVQL 96

C-terminal SARAH domain found in Ras-association domain-containing protein 4 (RASSF4); RASSF4 is one of six related proteins, the classical RASSF proteins (RASSF1-6), that contain a conserved RalGDS/AF6 Ras association (RA) domain located towards the C-terminus. It acts as a potential tumor suppressor that may promote apoptosis and cell cycle arrest. It also functions as a KRAS effector protein. RASSF4 is broadly expressed in normal tissues. Its expression is reduced in tumor cell lines and primary tumors by promoter specific hypermethylation. RASSF4 contains the RA and SARAH (Salvador-RassF-Hippo) domains. The RA domain of the classical RASSF proteins has a beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin. RA domains mediate interactions with Ras and other small GTPases, and SARAH domains mediate protein-protein interactions crucial in the pathways that induce cell cycle arrest and apoptosis. This model corresponds to the SARAH domain of RASSF4.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 1034638728 187 QYINFHFSLLESILQRLNEEEKREIQRIVTKFNKEKAIILKCLQNK 232
Cdd:cd21894     1 QYIKFEMPVLDSFVEKLKEEEEREIIKLTRKYSALRSMILQQLEQL 46

Ras-associating (RA) domain found in Ras-association domain-containing protein 3 (RASSF3); RASSF3 is a member of a family of six related classical RASSF1-6 proteins (the classical RASSF proteins). RASSF3 has three transcripts (A-C) due to alternative splicing of the exons. The RASSF3B and 3C isoforms are shorter than RASSF3A, and unlike RASSF3A do not contain the RA or SARAH domains. The RA domain of the classical RASSF proteins has a beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin. The RA domain mediates interactions with Ras and other small GTPases, and the SARAH domain mediates protein-protein interactions crucial in the pathways that induce cell cycle arrest and apoptosis. RASSF3A regulates apoptosis and cell cycle via p53 stabilization and possibly is involved in DNA repair.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1034638728  91 NHETSIFIPAfESETKVRVNSNMRTEEVIKQLLQKFKIENSPQDFALHIIFATGEQR---RLKKTDIPLLQRLLQGPS 165
Cdd:cd17219    54 NNETAFYLPK-GSVNTLHISSTNTVREVIEALLKKFLVADNPAKFALYKRCHKEDQVyacKLSDREHPLYLRLVAGPN 130

Ras-associating (RA) domain of Ras and Rab interactor (Rin) protein family; Family of Ras-interaction/interference (Rin) proteins, also known as Ras and Rab interactors, is composed of Rin1, Rin2, and Rin3, which have multifunctional domains, including SH2 and proline-rich domains in the N-terminal region, and RH, VPS9, and RA domains in the C-terminal region. RA domain-containing proteins function by interacting with Ras proteins directly or indirectly and are involved in several different functions ranging from tumor suppression to being oncoproteins. Ras proteins are small GTPases that are involved in cellular signal transduction. The RA domain has the beta-grasp ubiquitin-like (Ubl) fold with low sequence similarity to ubiquitin; ubiquitin is a protein modifier in eukaryotes that is involved in various cellular processes including transcriptional regulation, cell cycle control, and DNA repair. The RA domains of Rin1, Rin2, and Rin3 are well conserved and they all have Ras binding characteristics.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 1034638728 112 NMRTEEVIKQLLQKFKIENsPQDFALHIIfATGEQRRLKKTDIPLL 157
Cdd:cd01776    26 SMTAREVCKMIAHKFRVTN-PQDYGLFLL-VDGEEIQLEDNECPQL 69