C-terminal SARAH domain found in Ras-association domain-containing protein 2 (RASSF2); RASSF2 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 is a KRAS-specific effector protein. It stabilizes STK3/MST2 by protecting it from proteasomal degradation. 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 (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 RASSF2.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 1034626113 274 QYIKFEMPVLKSFIQKLQEEEDREVKKLMRKYTVLRLMIRQRLEEI 319
Cdd:cd21893     1 QYIKFEMPVLKSFIQKLKEEEDREVKKLMRRYTVLRLMIEQRLQEI 46

C-terminal SARAH domain found in Ras-association domain-containing protein 2 (RASSF2); RASSF2 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 is a KRAS-specific effector protein. It stabilizes STK3/MST2 by protecting it from proteasomal degradation. 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 (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 RASSF2.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 1034626113 274 QYIKFEMPVLKSFIQKLQEEEDREVKKLMRKYTVLRLMIRQRLEEI 319
Cdd:cd21893     1 QYIKFEMPVLKSFIQKLKEEEDREVKKLMRRYTVLRLMIEQRLQEI 46

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 1034626113 176 YNHKTSVFTPAYGSVT---NVRINSTMTTPQVLKLLLNKFKIENSAEEFALYVVHTSGEKQ-KLKATDYPLIARILQGPC 251
Cdd:pfam00788   1 DDGVLKVYTEDGKPGTtykTILVSSSTTAEEVIEALLEKFGLEDDPRDYVLVEVLERGGGErRLPDDECPLQIQLQWPRD 80

                          90
                  ....*....|...
gi 1034626113 252 EQISKVFLMEKDQ 264
Cdd:pfam00788  81 ASDSRFLLRKRDD 93

Ras-associating (RA) domain found in Ras-association domain family members, RASSF2, RASSF4, and RASSF6; The RASSF family of proteins shares a conserved RalGDS/AF6 RA domain either in the C-terminus (RASSF1-6) or N-terminus (RASSF7-10). The classical family members (RASSF1-6) contain a conserved SARAH (Salvador/RASSF/Hpo) motif adjacent to the RA domain that functions as scaffolding and regulatory interactions. The RA domain of the classical RASSF protein family has the 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 protein family seem to modulate some of the growth inhibitory responses mediated by Ras and may serve as tumor suppressor genes. This family contains RASSF2, RASSF4, and RASSF6.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034626113 177 NHKTSVFTPAYGSVTNVRINSTMTTPQVLKLLLNKFKIENSAEEFALYVVHTSGEKQKLKATDYPLIARILQGPCEQISK 256
Cdd:cd01784     1 NRKTSVFTPPYGSVTNVRVTSLMTTPEVIKLLLEKFKVENSPEEFALYVVKDSGERRRLKDDDYPLLTRVLLGPSEDVAK 80

                  ....*..
gi 1034626113 257 VFLMEKD 263
Cdd:cd01784    81 IFIMERA 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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034626113 177 NHKTSVFTPAYGSVTNVRINSTMTTPQVLKLLLNKFKIENSAEEFALYVVHTSGEKQKLKATDYPLIARILQGPCEQISK 256
Cdd:cd17223     1 NYKTSVFTPAFGSETKVRINSNMTTQEVIKQLLQKFKIENSPNEFALYIIHATGEKKRLKNTDFPLWERLLQGPSGKIAK 80

                  ....*..
gi 1034626113 257 VFLMEKD 263
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. 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.)

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                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034626113  174 HFYNHKTSVFTPAYGSVTNVRINSTMTTPQVLKLLLNKFKIENSAEEFALYVVHTSGEKQKLKATDYPLIARILQGPCEQ 253
Cdd:smart00314   1 DTFVLRVYVDDLPGGTYKTLRVSSRTTARDVIQQLLEKFHLTDDPEEYVLVEVLPDGKERVLPDDENPLQLQKLWPRRGP 80

                           90
                   ....*....|
gi 1034626113  254 ISKVFLMEKD 263
Cdd:smart00314  81 NLRFVLRKRD 90

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 1034626113 274 QYIKFEMPVLKSFIQKLQEEEDREVKKLMRKYTVLRLMIRQRLEEI 319
Cdd:cd21894     1 QYIKFEMPVLDSFVEKLKEEEEREIIKLTRKYSALRSMILQQLEQL 46

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1034626113 187 YGSVTNVRINSTMTTPQVLKLLLNKFKIENSAEEFALYVVHTSGEK-QKLKATDYPLIARILQGPCEQISKVFLME 261
Cdd:cd17043    12 GSAYKSILVSSTTTAREVVQLLLEKYGLEEDPEDYSLYEVSEKQETeRVLHDDECPLLIQLEWGPQGTEFRFVLKR 87

C-terminal SARAH domain found in scaffold protein salvador (Sav), Ras-association domain proteins, and mammalian STE20-like protein kinases (MST); The SARAH (Salvador-RassF-Hippo) domain family includes scaffold protein salvador (Sav), Ras-association domain proteins (RASSF1-6), and mammalian STE20-like protein kinase (MST) subfamily members (MST1-2 and Hippo). Sav is a scaffold protein mainly found in metazoans. Drosophila melanogaster Sav, also called Shar-pei (SHRP), promotes both cell cycle exit and apoptosis in Drosophila. It plays a key role in the Hippo/SWH (Sav/Wts/Hpo) signaling pathway. Human protein salvador homolog 1, also called 45 kDa WW domain protein (WW45), acts as a mammalian sterile 20-like kinase 1 (MST1)-binding protein required to enhance MST1-mediated apoptosis. It is a regulator of STK3/MST2 and STK4/MST1 in the Hippo signaling pathway. Classical RASSF proteins interact either directly or indirectly with activated Ras. Ras proteins are small GTPases that are involved in cellular signal transduction. They seem to modulate some of the growth inhibitory responses mediated by Ras and may serve as tumor suppressor genes. RASSF1-6 contains a conserved SARAH motif adjacent to the RA domain that functions in scaffolding and regulatory interactions. MST1/2 and Hippo are involved in a conserved pathway that governs cell contact inhibition, organ size control, and tumor development. MST1 and MST2 are STE20 family stress-activated, pro-apoptotic serine/threonine-protein kinases which, following caspase-cleavage, enter the nucleus and induces chromatin condensation followed by internucleosomal DNA fragmentation. They are key components of the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. Hippo (Hpo), also called STE20-like kinase MST (dMST), is the Drosophila homolog of STE20-like protein kinases, MST1 and MST2. It is a STE20 family serine/threonine-protein kinase that functions as a tumor suppressor by restricting cell proliferation and promotes apoptosis in conjunction with salvador and warts. Hpo also plays a key role in the Hippo/SWH signaling pathway. This model corresponds to the C-terminal SARAH domain, a characteristic coiled-coil structure. It is a small helical module that is important in signal-transduction networks. The central function of the SARAH domain seems to be the mediation of homo- and heterodimerization between SARAH domain-containing proteins.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 1034626113 274 QYIKFEMPVLKSFIQKLQEEEDREVKKLMRKYTVLRLMIRQRLEE 318
Cdd:cd21883     1 QLKNFSLPELQMFLKMLDPEEEREIEQLVKKYTAYRQAILDALEE 45

Ras-associating (RA) domain of Ras-association domain family 5 (RASSF5); RASSF5, also called New ras effector 1 (NORE1), or regulator for cell adhesion and polarization enriched in lymphoid tissues (RAPL), is a member of a family of six related RASSF1-6 proteins (the classical RASSF proteins) and is expressed as three transcripts (A-C) via differential promoter usage and alternative splicing. All transcripts variants of RASSF5 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. RASSF5A is a pro-apoptotic Ras effector and functions as a Ras regulated tumor suppressor. RASSF5C is regulated by Ras related protein and modulates cellular adhesion.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1034626113 177 NHKTSVFTPAyGSVTNVRINSTMTTPQVLKLLLNKFKIENSAEEFAL-YVVHTSGEK--QKLKATDYPLIARILQGP 250
Cdd:cd17220    65 DKRTSFYLPL-DAIKQLHISSTTTVSEVIQGLLKKFMVVDNPQKFALfKRMRKDGQVlfQKLPLTEYPLYLRLLAGP 140

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
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1034626113 193 VRINSTMTTPQVLKLLLNKFKIEN---SAEEFALYVVHTSGEKQKLKATDYPLI 243
Cdd:cd01782    40 IRVSSTATTQDVIETLIEKFRPDMrmlSNPRYSLYEVHPNGEERKLDDDEKPLV 93

Ras-associating (RA) domain found in Ras-association domain-containing protein 1 (RASSF1); RASSF1 is a member of a family of six related RASSF1-6 proteins (the classical RASSF proteins). RASSF1 has eight transcripts (A-H) arising from alternative splicing and differential promoter usage. With the exception of some minor splice variants (RASSF1F and RASSF1G), RASSF1 contains an RA domain and a C-terminal SARAH protein-protein interaction motif. 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. RASSF1A and 1C are the most extensively studied RASSF1 with both localized to microtubules and involved in regulation of growth and migration.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034626113 179 KTSVFTPAyGSVTNVRINSTMTTPQVLKLLLNKFKIENSAEEFALYVVHTSGEK---QKLKATDYPLIARILQGPCEQIS 255
Cdd:cd17218    72 RTSFYLPK-DTVKHLHISSKTRASEVIEALLKKFTVVDNPRKFALFERTEKDDQvylRKLSDDEQPLYLRLLAGPNEKTL 150

                  ....*.
gi 1034626113 256 KVFLME 261
Cdd:cd17218   151 SFVLKE 156

C-terminal SARAH domain found in Ras-association domain-containing protein 1 (RASSF1); RASSF1 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 is required for death receptor-dependent apoptosis. It mediates activation of STK3/MST2 and STK4/MST1 during Fas-induced apoptosis by preventing their dephosphorylation. RASSF1 has eight transcripts (A-H) arising from alternative splicing and differential promoter usage. RASSF1A and 1C are the most extensively studied RASSF1, with both localized to microtubules and involved in regulation of growth and migration. With the exception of some minor splice variants (RASSF1F and RASSF1G), RASSF1 contains an RA domain and a C-terminal SARAH (Salvador-RassF-Hippo) protein-protein interaction motif. 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. This model corresponds to the SARAH domain of RASSF1.

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 1034626113 278 FEMPVLKSFIQKLQEEEDREVKKLMRKYTVLRLMIRQRL 316
Cdd:cd21890     5 FSMPELQNFLRILQREEEEHVRQILQRYTRCREKMQEAL 43

Ras-associating (RA) domain found in Rho GTPase-activating protein 20 (RHG20) and similar proteins; RHG20, also termed ARHGAP20, is one of GTPase activating proteins for Rho family proteins (RhoGAPs). It contains a PH-like domain, an RA domain, a RhoGap domain, and two Annexin-like (ANXL) repeats. RA domain has the beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin that is a protein modifier in eukaryotes that is involved in various cellular processes including transcriptional regulation, cell cycle control, and DNA repair in eukaryotes.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1034626113 186 AYGSVTNVRINSTMTTPQVLKLLLNKFKIENSAEEFALYVVhtSGEKQKLkatdYPLI 243
Cdd:cd17115    14 SCAYSKTLTVSNTDTAKDVIKMALQQFGITGDPSDYQLWVK--SGKEESP----YPLI 65