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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148226372  64 LSKAETDQKIKDYNAQIKSNLFMSLNKDGSFTGFIKVQLKLVRPVSVAASKKPSCLQD-RKGSGRSQPVKRRTSFYLPKD 142
Cdd:cd17218    1 LSQAEIEQKIKEYNAQINSNLFMSLNKDGSYTGFIKVQLKLVRPVSVPANKKPSSIQDsRKGSGRSQPVKRRTSFYLPKD 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 148226372 143 ASKHLHLSSKTPASEVIQALLKKFTVLDNPRKFALFERTEKGGQVSLRKLTDDEEPLKLRLLSGPCEKTLSFVLKEN 219
Cdd:cd17218   81 TVKHLHISSKTRASEVIEALLKKFTVVDNPRKFALFERTEKDDQVYLRKLSDDEQPLYLRLLAGPNEKTLSFVLKEN 157

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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148226372  64 LSKAETDQKIKDYNAQIKSNLFMSLNKDGSFTGFIKVQLKLVRPVSVAASKKPSCLQD-RKGSGRSQPVKRRTSFYLPKD 142
Cdd:cd17218    1 LSQAEIEQKIKEYNAQINSNLFMSLNKDGSYTGFIKVQLKLVRPVSVPANKKPSSIQDsRKGSGRSQPVKRRTSFYLPKD 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 148226372 143 ASKHLHLSSKTPASEVIQALLKKFTVLDNPRKFALFERTEKGGQVSLRKLTDDEEPLKLRLLSGPCEKTLSFVLKEN 219
Cdd:cd17218   81 TVKHLHISSKTRASEVIEALLKKFTVVDNPRKFALFERTEKDDQVYLRKLSDDEQPLYLRLLAGPNEKTLSFVLKEN 157

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 148226372   131 VKRRTSFYLPKDASKHLHLSSKTPASEVIQALLKKFTVLDNPRKFALFERTEkggQVSLRKLTDDEEPLKLRLLSGPCEK 210
Cdd:smart00314   4 VLRVYVDDLPGGTYKTLRVSSRTTARDVIQQLLEKFHLTDDPEEYVLVEVLP---DGKERVLPDDENPLQLQKLWPRRGP 80

                           90
                   ....*....|
gi 148226372   211 TLSFVLKENE 220
Cdd:smart00314  81 NLRFVLRKRD 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148226372  135 TSFYLPKDASKHLHLSSKTPASEVIQALLKKFTVLDNPRKFALFERTEKGGQVslRKLTDDEEPLKLRLLSGPCEKTLSF 214
Cdd:pfam00788   9 TEDGKPGTTYKTILVSSSTTAEEVIEALLEKFGLEDDPRDYVLVEVLERGGGE--RRLPDDECPLQIQLQWPRDASDSRF 86

                  ....*..
gi 148226372  215 VLKENET 221
Cdd:pfam00788  87 LLRKRDD 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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148226372  64 LSKAETDQKIKDYNAQIKSNLFMSLNKDGSFTGFIKVQLKLVRPVSVAASKKPSCLQD-RKGSGRSQPVKRRTSFYLPKD 142
Cdd:cd17218    1 LSQAEIEQKIKEYNAQINSNLFMSLNKDGSYTGFIKVQLKLVRPVSVPANKKPSSIQDsRKGSGRSQPVKRRTSFYLPKD 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 148226372 143 ASKHLHLSSKTPASEVIQALLKKFTVLDNPRKFALFERTEKGGQVSLRKLTDDEEPLKLRLLSGPCEKTLSFVLKEN 219
Cdd:cd17218   81 TVKHLHISSKTRASEVIEALLKKFTVVDNPRKFALFERTEKDDQVYLRKLSDDEQPLYLRLLAGPNEKTLSFVLKEN 157

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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148226372  68 ETDQKIKDYNAQIKSNLFMSLNKDGSFTGFIKVQLKLVRPVSVAASKKPsclQDRKGSGRSQPVKRRTSFYLPKDASKHL 147
Cdd:cd17220    4 EIKQKIESYNTKVKNCLGMKLSPDGTYTGFIKVHLKLRRPVTVPAGIRP---QSIYEVNPADTTDKRTSFYLPLDAIKQL 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 148226372 148 HLSSKTPASEVIQALLKKFTVLDNPRKFALFERTEKGGQVSLRKLTDDEEPLKLRLLSGPCEKTLSFVLKEN 219
Cdd:cd17220   81 HISSTTTVSEVIQGLLKKFMVVDNPQKFALFKRMRKDGQVLFQKLPLTEYPLYLRLLAGPDTDVLSFVLKEN 152

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        40
                 ....*....|....*....|....*....|....*....|....*.
gi 148226372 225 NWDAFSMPELQNFLRILQREEEEHMRQIIQRYTRCREKMQEALASR 270
Cdd:cd21890    1 NWDAFSMPELQNFLRILQREEEEHVRQILQRYTRCREKMQEALASR 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 148226372   131 VKRRTSFYLPKDASKHLHLSSKTPASEVIQALLKKFTVLDNPRKFALFERTEkggQVSLRKLTDDEEPLKLRLLSGPCEK 210
Cdd:smart00314   4 VLRVYVDDLPGGTYKTLRVSSRTTARDVIQQLLEKFHLTDDPEEYVLVEVLP---DGKERVLPDDENPLQLQKLWPRRGP 80

                           90
                   ....*....|
gi 148226372   211 TLSFVLKENE 220
Cdd:smart00314  81 NLRFVLRKRD 90

C-terminal SARAH domain found in Ras-association domain-containing protein 5 (RASSF5); RASSF5, also called New ras effector 1 (NORE1), or regulator for cell adhesion and polarization enriched in lymphoid tissues (RAPL), 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 be involved in lymphocyte adhesion by linking RAP1A activation upon T-cell receptor or chemokine stimulation to integrin activation. RASSF5 is expressed as three transcripts (A-C) via differential promoter usage and alternative splicing. 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. All transcript variants of RASSF5 contain 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. 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 RASSF5, that mediates homo- and heterodimerization.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*...
gi 148226372 222 GEVNWDAFSMPELQNFLRILQREEEEHMRQIIQRYTRCREKMQEALAS 269
Cdd:cd21892    1 GEVEWDAFSVPELQNFLRILEKEEQDKIQQVQKKYAKFRQKLQDALKE 48

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 148226372  135 TSFYLPKDASKHLHLSSKTPASEVIQALLKKFTVLDNPRKFALFERTEKGGQVslRKLTDDEEPLKLRLLSGPCEKTLSF 214
Cdd:pfam00788   9 TEDGKPGTTYKTILVSSSTTAEEVIEALLEKFGLEDDPRDYVLVEVLERGGGE--RRLPDDECPLQIQLQWPRDASDSRF 86

                  ....*..
gi 148226372  215 VLKENET 221
Cdd:pfam00788  87 LLRKRDD 93

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 148226372 140 PKDASKHLHLSSKTPASEVIQALLKKFTVLDNPRKFALFERTEKGGqvSLRKLTDDEEPLKLRLLSGPCEKTLSFVLKE 218
Cdd:cd17043   11 PGSAYKSILVSSTTTAREVVQLLLEKYGLEEDPEDYSLYEVSEKQE--TERVLHDDECPLLIQLEWGPQGTEFRFVLKR 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 148226372 226 WDAFSMPELQNFLRILQREEEEHMRQIIQRYTRCREKMQEAL 267
Cdd:cd21883    2 LKNFSLPELQMFLKMLDPEEEREIEQLVKKYTAYRQAILDAL 43

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 148226372 134 RTSFYLPKDAS-KHLHLSSKTPASEVIQALLKKFTVLDNPRKFALFERTEKGGQvslRKLTDDEEPLKLRLLSGPCEKTL 212
Cdd:cd17221    3 KTSVFTPAYGSvTNVRINSTMTTPQVLKLLLNKFKIENSAEEFALYIVHTSGEK---QKLKATDYPLIARILQGPCEQVS 79

                 ....*...
gi 148226372 213 SFVLKENE 220
Cdd:cd17221   80 KVFLMEKD 87

Ras-associating (RA) domain 2 found in diacylgylcerol kinase theta (DAGK-theta) and similar proteins; DAGK phosphorylates the second messenger diacylglycerol to phosphatidic acid as part of a protein kinase C pathway. DAGK-theta is characterized as a type V DAGK that has three cysteine-rich domains (all other isoforms have two), a proline/glycine-rich domain at its N-terminal, and a proposed Ras-associating (RA) 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. There are ten mammalian isoforms of DAGK have been identified to date, these are organized into five categories based on the domain architecture. DAGK-theta also contains a pleckstrin homology (PH) domain. The subcellular localization and the activity of DAGK-theta are regulated in a complex (stimulation- and cell type-dependent) manner. This family corresponds to the second RA domain of DAGK-theta.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 148226372 142 DASKHLHLSSKTPASEVIQALLKKFTVLD-NPRKFALFERTEKGGQVSlRKLTDDEEPLKLRL 203
Cdd:cd01783   14 VAYKSIPVTKETTVEEVIKEALPKFGLQDeDPEDFRLVEVLMDKGVVE-RVMLRDECPWLILL 75