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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622862220 520 QHLLRVAYQDPSSGCTSKTLAVPPEASIATLNQLCATKFRVTQPNTFGLFLYKDQGYHRLPPGALARRLPT-------TG 592
Cdd:cd17215     1 QNFLRVAYQDPSSGCTSKTLAVPPSATVADLNQLCATKFKVTQPETYGIFLYKEQGYQRLPPDALPQRIKAqlkekgsTF 80

                  ....*...
gi 1622862220 593 YLVYRRAE 600
Cdd:cd17215    81 YFVYQRAE 88

Ras-associating (RA) domain found in Ras and Rab interactor 1 (Rin1); Rin1, also termed Ras inhibitor JC99, or Ras interaction/interference protein 1, is a downstream Ras effector that represents a unique class of Ras effector connected to two independent signaling pathways. The first effector pathway is the direct activation of RAB5-mediated endocytosis and the second pathway involves direct activation of ABL tyrosine kinase activity. Rin1 functions as a guanine nucleotide exchange factor (GEF) for RAB5 GTPases. The RAB5 GEF activity of Rin1 promotes early endosome fusion, an early event in transit to the lysosome. Rin1 binds the SH3 and SH2 domains of ABL proteins, ABL1 and ABL2, and activates their tyrosine kinase activity. Rin1 contains SH2 and proline-rich domains in the N-terminal region, and RH, VPS9, and RA domains in the C-terminal region. 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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622862220 520 QHLLRVAYQDPSSGCTSKTLAVPPEASIATLNQLCATKFRVTQPNTFGLFLYKDQGYHRLPPGALARRLPT-------TG 592
Cdd:cd17215     1 QNFLRVAYQDPSSGCTSKTLAVPPSATVADLNQLCATKFKVTQPETYGIFLYKEQGYQRLPPDALPQRIKAqlkekgsTF 80

                  ....*...
gi 1622862220 593 YLVYRRAE 600
Cdd:cd17215    81 YFVYQRAE 88

Vacuolar sorting protein 9 (VPS9) domain; This domain acts as a GDP-GTP exchange factor (GEF). It activates Rab GTPases by stimulating the release of GDP and allowing GTP to bind.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622862220 387 MEQVRQKLLQLLRTYSPSAQVKRLLQACKLLYMALRT-QEGEDAGADEFLPLLSLVLAHCDLPELLLEAEYMSELLEPSL 465
Cdd:pfam02204   1 WEQAQQELKKLNEAKSPREKLKCLLRTCKLITEALSKsNRDESLGADDLLPILIYVLIRANPPNLYSNLQFISEFRDPDL 80

                          90
                  ....*....|
gi 1622862220 466 LTGEGGYYLT 475
Cdd:pfam02204  81 LSGEEGYYLT 90

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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622862220 519 FQHLLRVAYQDPSSGCTSKTLAVPPEASIATLNQLCATKFRVTQ-PNTFGLFLYkdqgyhrLPPGALARRLPTTGYLVYR 597
Cdd:pfam00788   1 DDGVLKVYTEDGKPGTTYKTILVSSSTTAEEVIEALLEKFGLEDdPRDYVLVEV-------LERGGGERRLPDDECPLQI 73

                  ....*
gi 1622862220 598 RAEWP 602
Cdd:pfam00788  74 QLQWP 78

Ras-associating (RA) domain found in Ras and Rab interactor 1 (Rin1); Rin1, also termed Ras inhibitor JC99, or Ras interaction/interference protein 1, is a downstream Ras effector that represents a unique class of Ras effector connected to two independent signaling pathways. The first effector pathway is the direct activation of RAB5-mediated endocytosis and the second pathway involves direct activation of ABL tyrosine kinase activity. Rin1 functions as a guanine nucleotide exchange factor (GEF) for RAB5 GTPases. The RAB5 GEF activity of Rin1 promotes early endosome fusion, an early event in transit to the lysosome. Rin1 binds the SH3 and SH2 domains of ABL proteins, ABL1 and ABL2, and activates their tyrosine kinase activity. Rin1 contains SH2 and proline-rich domains in the N-terminal region, and RH, VPS9, and RA domains in the C-terminal region. 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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622862220 520 QHLLRVAYQDPSSGCTSKTLAVPPEASIATLNQLCATKFRVTQPNTFGLFLYKDQGYHRLPPGALARRLPT-------TG 592
Cdd:cd17215     1 QNFLRVAYQDPSSGCTSKTLAVPPSATVADLNQLCATKFKVTQPETYGIFLYKEQGYQRLPPDALPQRIKAqlkekgsTF 80

                  ....*...
gi 1622862220 593 YLVYRRAE 600
Cdd:cd17215    81 YFVYQRAE 88

Vacuolar sorting protein 9 (VPS9) domain; This domain acts as a GDP-GTP exchange factor (GEF). It activates Rab GTPases by stimulating the release of GDP and allowing GTP to bind.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622862220 387 MEQVRQKLLQLLRTYSPSAQVKRLLQACKLLYMALRT-QEGEDAGADEFLPLLSLVLAHCDLPELLLEAEYMSELLEPSL 465
Cdd:pfam02204   1 WEQAQQELKKLNEAKSPREKLKCLLRTCKLITEALSKsNRDESLGADDLLPILIYVLIRANPPNLYSNLQFISEFRDPDL 80

                          90
                  ....*....|
gi 1622862220 466 LTGEGGYYLT 475
Cdd:pfam02204  81 LSGEEGYYLT 90

Src homology 2 (SH2) domain found in Ras and Rab interactor (RIN)-family; The RIN (AKA Ras interaction/interference) family is composed of RIN1, RIN2 and RIN3. These proteins have multifunctional domains including SH2 and proline-rich (PR) domains in the N-terminal region, and RIN-family homology (RH), VPS9 and Ras-association (RA) domains in the C-terminal region. RIN proteins function as Rab5-GEFs, and RIN3 specifically functions as a Rab31-GEF. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

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                  ....*....|....*....|....*....|....*....|....*....|...
gi 1622862220   1 MRLPEASGPSFVSSHYILESPGGVSLEGSELMFPDLVQLICAYCHTRDILLLP 53
Cdd:cd10339    49 MRLPEASGPAFVSEHYIKESPGGVSLEGSELMFPDLFRLIAFYCHSRDILPFT 101

Ras-associating (RA) domain found in Ras and Rab interactor 3 (Rin3); Rin3, also termed Ras interaction/interference protein 3, is a RAS effector and a RAB5-activating guanine nucleotide exchange factor (GEF) specifically for GTPase Rab31. It functions as a negative regulator of mast cell responses to Stem Cell Factor (SCF). Rin3 contains the Vps9p-like guanine nucleotide exchange factor and Ras-association (RA) domains.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1622862220 520 QHLLRVAYQDPssGCTSKTLAVPPEASIATLNQLCATKFRVTQPNTFGLFLYKDQGYHRLPPGALARRL 588
Cdd:cd16130     1 QDFISVSFLEP--GSNTRTLAIRPDTTAEDLCKQCAEKFEVLDPENYGLFVLVDGRCLQLADDALPHHI 67

Src homology 2 (SH2) domain found in Ras and Rab interactor 2 (RIN2)-like proteins; RIN2, a member of the RIN (AKA Ras interaction/interference) family, have multifunctional domains including SH2 and proline-rich (PR) domains in the N-terminal region, and RIN-family homology (RH), VPS9 and Ras-association (RA) domains in the C-terminal region. RIN proteins function as Rab5-GEFs. Ras induces activation of Rab5 through RIN2, which is a direct downstream target of Ras and a direct upstream regulator of Rab5. In other words it is the binding of the GTP-bound form of Ras to the RA domain of RIN2 that enhances the GEF activity toward Rab5. It is thought that the RA domain negatively regulates the Rab5 GEF activity. In steady state, RIN2 is likely to form a closed conformation by an intramolecular interaction between the RA domain and the Vps9p-like (Rab5 GEF) domain, negatively regulating the Rab5 GEF activity. In the active state, the binding of Ras to the RA domain may reduce the intramolecular interaction and stabilize an open conformation of RIN2. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

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                  ....*....|....*....|....*....|....*....|....*....|
gi 1622862220   1 MRLPEASGpSFVSSHYILESPGGVSLEGSELMFPDLVQLICAYCHTRDIL 50
Cdd:cd10394    49 LRLPCEFG-APLKEFAIKESTYTFSLEGSGISFADLFRLIAFYCISRDVL 97

Src homology 2 (SH2) domain found in Ras and Rab interactor 3 (RIN3)-like proteins; RIN3, a member of the RIN (AKA Ras interaction/interference) family, have multifunctional domains including SH2 and proline-rich (PR) domains in the N-terminal region, and RIN-family homology (RH), VPS9 and Ras-association (RA) domains in the C-terminal region. RIN proteins function as Rab5-GEFs. RIN3 stimulated the formation of GTP-bound Rab31, a Rab5-subfamily GTPase, and formed enlarged vesicles and tubular structures, where it colocalized with Rab31. Transferrin appeared to be transported partly through the RIN3-positive vesicles to early endosomes. RIN3 interacts via its Pro-rich domain with amphiphysin II, which contains SH3 domain and participates in receptor-mediated endocytosis. RIN3, a Rab5 and Rab31 GEF, plays an important role in the transport pathway from plasma membrane to early endosomes. Mutations in the region between the SH2 and RH domain of RIN3 specifically abolished its GEF action on Rab31, but not Rab5. RIN3 was also found to partially translocate the cation-dependent mannose 6-phosphate receptor from the trans-Golgi network to peripheral vesicles and that this is dependent on its Rab31-GEF activity. These data indicate that RIN3 specifically acts as a GEF for Rab31. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1622862220   1 MRLPEASGPSFVSSHYILESPGGVSLEGSELMFPDLVQLICAYCHTRDILLLP 53
Cdd:cd10395    49 VHFPSNESSAEVLEYPIKEEKSILYLEGSVLVFEDIFKLIAFYCVSRDLLPFT 101