Src homology 2 (SH2) domain found in Ras and Rab interactor 1 (RIN1)-like proteins; RIN1, 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. Previous studies showed that RIN1 interacts with EGF receptors via its SH2 domain and regulates trafficking and degradation of EGF receptors via its interaction with STAM, indicating a vital role for RIN1 in regulating endosomal trafficking of receptor tyrosine kinases (RTKs). RIN1 was first identified as a Ras-binding protein that suppresses the activated RAS2 allele in S. cerevisiae. RIN1 binds to the activated Ras through its carboxyl-terminal domain and this Ras-binding domain also binds to 14-3-3 proteins as Raf-1 does. The SH2 domain of RIN1 are thought to interact with the phosphotyrosine-containing proteins, but the physiological partners for this domain are unknown. The proline-rich domain in RIN1 is similar to the consensus SH3 binding regions. 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        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 28202254  57 LRERLLITRPVWLQLRANAAAALHVLRTEPPGTFLVRKSNTRQCQTLCVRLPEASGPSFVSSHYLQESPGGISLEGSELT 136
Cdd:cd10393   1 LRERLLLTRPVWLQLRANAAAALHVLRTEPPGTFLVRKSNTRQCQALCVRLPEASGPSFVSSHYIQESPGGVSLEGSELT 80

                        90       100
                ....*....|....*....|.
gi 28202254 137 FPDLVQLICAYCHTRDILLLP 157
Cdd:cd10393  81 FPDLVQLICAYCHTRDILLLP 101

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 28202254 625 QHLLRVAYQDPSTGCTSKTLAVPPGSSIATLSQLCATKFRVTQPDAFGLFLYKDQGYHRLPPEALVHRLPT-------TG 697
Cdd:cd17215   1 QNFLRVAYQDPSSGCTSKTLAVPPSATVADLNQLCATKFKVTQPETYGIFLYKEQGYQRLPPDALPQRIKAqlkekgsTF 80

                ....*...
gi 28202254 698 YLIYRRAE 705
Cdd:cd17215  81 YFVYQRAE 88

Src homology 2 (SH2) domain found in Ras and Rab interactor 1 (RIN1)-like proteins; RIN1, 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. Previous studies showed that RIN1 interacts with EGF receptors via its SH2 domain and regulates trafficking and degradation of EGF receptors via its interaction with STAM, indicating a vital role for RIN1 in regulating endosomal trafficking of receptor tyrosine kinases (RTKs). RIN1 was first identified as a Ras-binding protein that suppresses the activated RAS2 allele in S. cerevisiae. RIN1 binds to the activated Ras through its carboxyl-terminal domain and this Ras-binding domain also binds to 14-3-3 proteins as Raf-1 does. The SH2 domain of RIN1 are thought to interact with the phosphotyrosine-containing proteins, but the physiological partners for this domain are unknown. The proline-rich domain in RIN1 is similar to the consensus SH3 binding regions. 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        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 28202254  57 LRERLLITRPVWLQLRANAAAALHVLRTEPPGTFLVRKSNTRQCQTLCVRLPEASGPSFVSSHYLQESPGGISLEGSELT 136
Cdd:cd10393   1 LRERLLLTRPVWLQLRANAAAALHVLRTEPPGTFLVRKSNTRQCQALCVRLPEASGPSFVSSHYIQESPGGVSLEGSELT 80

                        90       100
                ....*....|....*....|.
gi 28202254 137 FPDLVQLICAYCHTRDILLLP 157
Cdd:cd10393  81 FPDLVQLICAYCHTRDILLLP 101

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 28202254 625 QHLLRVAYQDPSTGCTSKTLAVPPGSSIATLSQLCATKFRVTQPDAFGLFLYKDQGYHRLPPEALVHRLPT-------TG 697
Cdd:cd17215   1 QNFLRVAYQDPSSGCTSKTLAVPPSATVADLNQLCATKFKVTQPETYGIFLYKEQGYQRLPPDALPQRIKAqlkekgsTF 80

                ....*...
gi 28202254 698 YLIYRRAE 705
Cdd:cd17215  81 YFVYQRAE 88

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 28202254    624 FQHLLRVAYQDPStGCTSKTLAVPPGSSIATLSQLCATKFRVT-QPDAFGLFLYKDQG-YHRLPPEALVHRL-------- 693
Cdd:smart00314   1 DTFVLRVYVDDLP-GGTYKTLRVSSRTTARDVIQQLLEKFHLTdDPEEYVLVEVLPDGkERVLPDDENPLQLqklwprrg 79

                           90
                   ....*....|
gi 28202254    694 PTTGYLIYRR 703
Cdd:smart00314  80 PNLRFVLRKR 89

SH2 domain;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 28202254    72 RANAAAALhvLRTEPPGTFLVRKSNTRQCQ-TLCVRLPEasgpsfVSSHYL-QESPGGISLEGSELTFPDLVQLI 144
Cdd:pfam00017   8 RQEAERLL--LNGKPDGTFLVRESESTPGGyTLSVRDDG------KVKHYKiQSTDNGGYYISGGVKFSSLAELV 74

Src homology 2 (SH2) domain found in Ras and Rab interactor 1 (RIN1)-like proteins; RIN1, 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. Previous studies showed that RIN1 interacts with EGF receptors via its SH2 domain and regulates trafficking and degradation of EGF receptors via its interaction with STAM, indicating a vital role for RIN1 in regulating endosomal trafficking of receptor tyrosine kinases (RTKs). RIN1 was first identified as a Ras-binding protein that suppresses the activated RAS2 allele in S. cerevisiae. RIN1 binds to the activated Ras through its carboxyl-terminal domain and this Ras-binding domain also binds to 14-3-3 proteins as Raf-1 does. The SH2 domain of RIN1 are thought to interact with the phosphotyrosine-containing proteins, but the physiological partners for this domain are unknown. The proline-rich domain in RIN1 is similar to the consensus SH3 binding regions. 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        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 28202254  57 LRERLLITRPVWLQLRANAAAALHVLRTEPPGTFLVRKSNTRQCQTLCVRLPEASGPSFVSSHYLQESPGGISLEGSELT 136
Cdd:cd10393   1 LRERLLLTRPVWLQLRANAAAALHVLRTEPPGTFLVRKSNTRQCQALCVRLPEASGPSFVSSHYIQESPGGVSLEGSELT 80

                        90       100
                ....*....|....*....|.
gi 28202254 137 FPDLVQLICAYCHTRDILLLP 157
Cdd:cd10393  81 FPDLVQLICAYCHTRDILLLP 101

Domain present in VPS9; Domain present in yeast vacuolar sorting protein 9 and other proteins.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 28202254    489 PVEIEPVRQKLLQLLRaySPSAQIKWLLQACKLLYTALKTQAGENAGADEFLPLLSLVLAQCDLPDLLLEAEYMSELLEP 568
Cdd:smart00167   1 FVEIEQIELKFLQLYK--SPSDKIKCLLRACKLIYTLLETQSGEVAGADDFLPVLIYVIIKCDPRDLLLNAEYMEEFLEP 78

                           90       100       110
                   ....*....|....*....|....*....|....*....
gi 28202254    569 TLLTGEGGYYLTSLSASLALLSGLSQAHALPLSPAQELQ 607
Cdd:smart00167  79 SLLTGEGGYYLTSLSAALALIKGLTEAHALPLSPEQELE 117

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 28202254   492 IEPVRQKLLQLLRAYSPSAQIKWLLQACKLLYTAL-KTQAGENAGADEFLPLLSLVLAQCDLPDLLLEAEYMSELLEPTL 570
Cdd:pfam02204   1 WEQAQQELKKLNEAKSPREKLKCLLRTCKLITEALsKSNRDESLGADDLLPILIYVLIRANPPNLYSNLQFISEFRDPDL 80

                          90
                  ....*....|
gi 28202254   571 LTGEGGYYLT 580
Cdd:pfam02204  81 LSGEEGYYLT 90

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        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 28202254  59 ERLLITRPVWLQLRANAAAALHVLRTEPPGTFLVRKSNTRQCQTLCVRLPEASGPSFVSSHYLQESPGGISLEGSELTFP 138
Cdd:cd10395   3 EKLIKTCPVWLQLGMNQAEAARILHKEVAGMFLVRRDSNSKQMVLCVHFPSNESSAEVLEYPIKEEKSILYLEGSVLVFE 82

                        90
                ....*....|....*
gi 28202254 139 DLVQLICAYCHTRDI 153
Cdd:cd10395  83 DIFKLIAFYCVSRDL 97

Ras-associating (RA) domain found in Ras and Rab interactor 2 (Rin2); Rin2, also termed Ras association domain family 4, or Ras inhibitor JC265, or Ras interaction/interference protein 2, is a Rab5 GDP/GTP exchange factor with the Vps9p-like guanine nucleotide exchange factor and Ras-association (RA) domains. Rin2 connects three GTPases, R-Ras, Rab5 and Rac1, to promote endothelial cell adhesion through the regulation of integrin internalization and Rac1 activation. Rin2 is involved in the regulation of Rab5-mediated early endocytosis. The deficiency of Rin2 can cause the RIN2 syndrome, an autosomal recessive connective tissue disorder.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 28202254 624 FQHLLRVAYQDPSTGCTSKTLAVPPGSSIATLSQLCATKFRVTQPDAFGLFLYKDQGYHRLPPEALVHRL---------P 694
Cdd:cd16131   1 FQNYLRVAFQEVNSGCTAKTLLVRPYTTTEEVCQLCAQKFKVQDPENYSLFLLIDDTWQQLAEDTYPQKIkaelhsrpqP 80

                ....*....
gi 28202254 695 TTGYLIYRR 703
Cdd:cd16131  81 QIFHFVYKR 89

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 28202254    624 FQHLLRVAYQDPStGCTSKTLAVPPGSSIATLSQLCATKFRVT-QPDAFGLFLYKDQG-YHRLPPEALVHRL-------- 693
Cdd:smart00314   1 DTFVLRVYVDDLP-GGTYKTLRVSSRTTARDVIQQLLEKFHLTdDPEEYVLVEVLPDGkERVLPDDENPLQLqklwprrg 79

                           90
                   ....*....|
gi 28202254    694 PTTGYLIYRR 703
Cdd:smart00314  80 PNLRFVLRKR 89

Src homology 2 (SH2) domain; In general, SH2 domains are involved in signal transduction; they bind pTyr-containing polypeptide ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites. They are present in a wide array of proteins including: adaptor proteins (Nck1, Crk, Grb2), scaffolds (Slp76, Shc, Dapp1), kinases (Src, Syk, Fps, Tec), phosphatases (Shp-1, Shp-2), transcription factors (STAT1), Ras signaling molecules (Ras-Gap), ubiquitination factors (c-Cbl), cytoskeleton regulators (Tensin), signal regulators (SAP), and phospholipid second messengers (PLCgamma), amongst others.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 28202254  68 WLQLRANAAAALHVLRTEPPGTFLVRKSNTRQ-CQTLCVRlpeaSGPSFVsSHYL--QESPGGISLEGSELTFPDLVQLI 144
Cdd:cd00173   2 WFHGSISREEAERLLRGKPDGTFLVRESSSEPgDYVLSVR----SGDGKV-KHYLieRNEGGYYLLGGSGRTFPSLPELV 76

                ...
gi 28202254 145 CAY 147
Cdd:cd00173  77 EHY 79

Src homology 2 domain found in Tensin-like proteins; SH2 domain found in Tensin-like proteins. The Tensins are a family of intracellular proteins that interact with receptor tyrosine kinases (RTKs), integrins, and actin. They are thought act as signaling bridges between the extracellular space and the cytoskeleton. There are four homologues: Tensin1, Tensin2 (TENC1, C1-TEN), Tensin3 and Tensin4 (cten), all of which contain a C-terminal tandem SH2-PTB domain pairing, as well as actin-binding regions that may localize them to focal adhesions. The isoforms of Tensin2 and Tensin3 contain N-terminal C1 domains, which are atypical and not expected to bind to phorbol esters. Tensins 1-3 contain a phosphatase (PTPase) and C2 domain pairing which resembles PTEN (phosphatase and tensin homologue deleted on chromosome 10) protein. PTEN is a lipid phosphatase that dephosphorylates phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) to yield phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). As PtdIns(3,4,5)P3 is the product of phosphatidylinositol 3-kinase (PI3K) activity, PTEN is therefore a key negative regulator of the PI3K pathway. Because of their PTEN-like domains, the Tensins may also possess phosphoinositide-binding or phosphatase capabilities. However, only Tensin2 and Tensin3 have the potential to be phosphatases since only their PTPase domains contain a cysteine residue that is essential for catalytic activity. 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        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 28202254  64 TRPVWLQLRANAAAALHVLRTEPPGTFLVRKSNTRQ-CQTLCVR--------LPEASGPSFVSS---HYLQE-SPGGISL 130
Cdd:cd09927   1 TSKYWYKPNISRDQAIALLKDKPPGTFLVRDSTTYKgAYGLAVKvatpppgvNPFEAKGDPESElvrHFLIEpSPKGVKL 80

                        90       100
                ....*....|....*....|..
gi 28202254 131 EG--SELTFPDLVQLICAYCHT 150
Cdd:cd09927  81 KGcpNEPVFGSLSALVYQHSIT 102

SH2 domain;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 28202254    72 RANAAAALhvLRTEPPGTFLVRKSNTRQCQ-TLCVRLPEasgpsfVSSHYL-QESPGGISLEGSELTFPDLVQLI 144
Cdd:pfam00017   8 RQEAERLL--LNGKPDGTFLVRESESTPGGyTLSVRDDG------KVKHYKiQSTDNGGYYISGGVKFSSLAELV 74