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 928168732 770 FQNYLRVAFQEVNSGCTGKTLLVRPYVTTEDVCQLCAEKFKVGDPEEYSLFLFVDETWQQLAEDTYPQKIKAELHSRPQP 849
Cdd:cd16131    1 FQNYLRVAFQEVNSGCTAKTLLVRPYTTTEEVCQLCAQKFKVQDPENYSLFLLIDDTWQQLAEDTYPQKIKAELHSRPQP 80

                         90
                 ....*....|.
gi 928168732 850 HIFHFVYKRIK 860
Cdd:cd16131   81 QIFHFVYKRIP 91

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
                 ....*....|....*....|....*....|....
gi 928168732 124 ILDRLLHTHPIWLQLSLSEEEAAQVLRSQPPGPF 157
Cdd:cd10394    1 ILDRLLHTHPIWLQLSLSEEEAAEVLQAQPPGIF 34

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 928168732 770 FQNYLRVAFQEVNSGCTGKTLLVRPYVTTEDVCQLCAEKFKVGDPEEYSLFLFVDETWQQLAEDTYPQKIKAELHSRPQP 849
Cdd:cd16131    1 FQNYLRVAFQEVNSGCTAKTLLVRPYTTTEEVCQLCAQKFKVQDPENYSLFLLIDDTWQQLAEDTYPQKIKAELHSRPQP 80

                         90
                 ....*....|.
gi 928168732 850 HIFHFVYKRIK 860
Cdd:cd16131   81 QIFHFVYKRIP 91

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 928168732  634 VEKIKVKFMTMQKMYSPEKKVMLLLRVCKLIYTVMEN-NSGRMYGADDFLPVLTYVIAQCDMLELDTEIEYMMELLDPSL 712
Cdd:pfam02204   1 WEQAQQELKKLNEAKSPREKLKCLLRTCKLITEALSKsNRDESLGADDLLPILIYVLIRANPPNLYSNLQFISEFRDPDL 80

                          90       100
                  ....*....|....*....|...
gi 928168732  713 LHGEGGYYLTSAYGALSLIKNFQ 735
Cdd:pfam02204  81 LSGEEGYYLTTLEAALEFIESLD 103

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.

                         10        20        30
                 ....*....|....*....|....*....|....
gi 928168732 124 ILDRLLHTHPIWLQLSLSEEEAAQVLRSQPPGPF 157
Cdd:cd10394    1 ILDRLLHTHPIWLQLSLSEEEAAEVLQAQPPGIF 34

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 928168732 770 FQNYLRVAFQEVNSGCTGKTLLVRPYVTTEDVCQLCAEKFKVGDPEEYSLFLFVDETWQQLAEDTYPQKIKAELHSRPQP 849
Cdd:cd16131    1 FQNYLRVAFQEVNSGCTAKTLLVRPYTTTEEVCQLCAQKFKVQDPENYSLFLLIDDTWQQLAEDTYPQKIKAELHSRPQP 80

                         90
                 ....*....|.
gi 928168732 850 HIFHFVYKRIK 860
Cdd:cd16131   81 QIFHFVYKRIP 91

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        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 928168732 771 QNYLRVAFQEVNSGC-TGKTLLVRPYVTTEDVCQLCAEKFKVGDPEEYSLFLFVDETWQQLAEDTYPQKIKAELHSRPQP 849
Cdd:cd01776    1 QGFLRVAVPDENNGSiVSKTLPVRPSMTAREVCKMIAHKFRVTNPQDYGLFLLVDGEEIQLEDNECPQLIKGELLATSKK 80

                         90
                 ....*....|.
gi 928168732 850 HiFHFVYKRIK 860
Cdd:cd01776   81 P-CYFAYKRID 90

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 928168732  634 VEKIKVKFMTMQKMYSPEKKVMLLLRVCKLIYTVMEN-NSGRMYGADDFLPVLTYVIAQCDMLELDTEIEYMMELLDPSL 712
Cdd:pfam02204   1 WEQAQQELKKLNEAKSPREKLKCLLRTCKLITEALSKsNRDESLGADDLLPILIYVLIRANPPNLYSNLQFISEFRDPDL 80

                          90       100
                  ....*....|....*....|...
gi 928168732  713 LHGEGGYYLTSAYGALSLIKNFQ 735
Cdd:pfam02204  81 LSGEEGYYLTTLEAALEFIESLD 103

Ras-associating (RA) domain, structurally similar to a beta-grasp ubiquitin-like fold; RA domain-containing proteins function by interacting with Ras proteins directly or indirectly and are involved in various 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 (Ub); Ub is a protein modifier in eukaryotes that is involved in various cellular processes, including transcriptional regulation, cell cycle control, and DNA repair. RA-containing proteins include RalGDS, AF6, RIN, RASSF1, SNX27, CYR1, STE50, and phospholipase C epsilon.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 928168732 773 YLRVAFQEVNSGCTGKTLLVRPYVTTEDVCQLCAEKFKV-GDPEEYSLFLFVD--ETWQQLAEDTYPQKIKAElhSRPQP 849
Cdd:cd17043    1 VLKVYDDDLAPGSAYKSILVSSTTTAREVVQLLLEKYGLeEDPEDYSLYEVSEkqETERVLHDDECPLLIQLE--WGPQG 78

                 ....*....
gi 928168732 850 HIFHFVYKR 858
Cdd:cd17043   79 TEFRFVLKR 87

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.

                         10        20        30
                 ....*....|....*....|....*....|....
gi 928168732 124 ILDRLLHTHPIWLQLSLSEEEAAQVLRSQPPGPF 157
Cdd:cd10394    1 ILDRLLHTHPIWLQLSLSEEEAAEVLQAQPPGIF 34

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.

                         10        20        30
                 ....*....|....*....|....*....|....
gi 928168732 124 ILDRLLHTHPIWLQLSLSEEEAAQVLRSQPPGPF 157
Cdd:cd10339    1 LLERLLLTRPVWLQLQLNAAEAAHMLQTEPPGTF 34

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
                 ....*....|....*....|....*....|....
gi 928168732 124 ILDRLLHTHPIWLQLSLSEEEAAQVLRSQPPGPF 157
Cdd:cd10395    1 ILEKLIKTCPVWLQLGMNQAEAARILHKEVAGMF 34