Ras subfamily of RAS small GTPases; Similar in fold and function to the bacterial EF-Tu GTPase. p21Ras couples receptor Tyr kinases and G protein receptors to protein kinase cascades

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221330026    11 KVLVCGMKGVGKTALIEQLVYGHVNPETElhPTIEDIY--VASVDtgrgGARETLRIYDTAGlQGEQQQLPRHYLQFPDA 88
Cdd:smart00173   2 KLVVLGSGGVGKSALTIQFIQGHFVDDYD--PTIEDSYrkQIEID----GEVCLLDILDTAG-QEEFSAMRDQYMRTGEG 74

                           90       100       110
                   ....*....|....*....|....*....|....*....
gi 221330026    89 FVLVYDPMDPRSLDMLADIKADIEKHKEKKEIPVVVLAN 127
Cdd:smart00173  75 FLLVYSITDRQSFEEIKKFREQILRVKDRDDVPIVLVGN 113

GTPase SAR1 family domain [General function prediction only];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221330026  11 KVLVCGMKGVGKTALIEQLVYGHVNPETELhPTIE-DIYVASVDTGRGGARetLRIYDTAGlQGEQQQLPRHY---LQFP 86
Cdd:COG1100    5 KIVVVGTGGVGKTSLVNRLVGDIFSLEKYL-STNGvTIDKKELKLDGLDVD--LVIWDTPG-QDEFRETRQFYarqLTGA 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 221330026  87 DAFVLVYDPMDPRSLDMLADIKADIEKHkeKKEIPVVVLAN 127
Cdd:COG1100   81 SLYLFVVDGTREETLQSLYELLESLRRL--GKKSPIILVLN 119

Rab family protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221330026  11 KVLVCGMKGVGKTALIEQLVYGHVNpetELHPTIE-DIYVASVDTGrgGARETLRIYDTAGlQGEQQQLPRHYLQFPDAF 89
Cdd:PLN03118  16 KILLIGDSGVGKSSLLVSFISSSVE---DLAPTIGvDFKIKQLTVG--GKRLKLTIWDTAG-QERFRTLTSSYYRNAQGI 89

                         90
                 ....*....|....*...
gi 221330026  90 VLVYDPMDPRSLDMLADI 107
Cdd:PLN03118  90 ILVYDVTRRETFTNLSDV 107

Rat sarcoma (Ras) family of small guanosine triphosphatases (GTPases); The Ras family of the Ras superfamily includes classical N-Ras, H-Ras, and K-Ras, as well as R-Ras, Rap, Ral, Rheb, Rhes, ARHI, RERG, Rin/Rit, RSR1, RRP22, Ras2, Ras-dva, and RGK proteins. Ras proteins regulate cell growth, proliferation and differentiation. Ras is activated by guanine nucleotide exchange factors (GEFs) that release GDP and allow GTP binding. Many RasGEFs have been identified. These are sequestered in the cytosol until activation by growth factors triggers recruitment to the plasma membrane or Golgi, where the GEF colocalizes with Ras. Active GTP-bound Ras interacts with several effector proteins: among the best characterized are the Raf kinases, phosphatidylinositol 3-kinase (PI3K), RalGEFs and NORE/MST1. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221330026  11 KVLVCGMKGVGKTALIEQLVYGHVNPETElhPTIEDIYVASVDTGrgGARETLRIYDTAGlQGEQQQLPRHYLQFPDAFV 90
Cdd:cd00876    1 KLVVLGAGGVGKSALTIRFVSGEFVEEYD--PTIEDSYRKQIVVD--GETYTLDILDTAG-QEEFSAMRDQYIRNGDGFI 75

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 221330026  91 LVYDPMDPRSLDMLADIKADIEKHKEKKEIPVVVLAN 127
Cdd:cd00876   76 LVYSITSRESFEEIKNIREQILRVKDKEDVPIVLVGN 112

Small GTPase of the Ras superfamily; ill-defined subfamily; SMART predicts Ras-like small GTPases of the ARF, RAB, RAN, RAS, and SAR subfamilies. Others that could not be classified in this way are predicted to be members of the small GTPase superfamily without predictions of the subfamily.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221330026    11 KVLVCGMKGVGKTALIEQLVYGHVNPETElhPTIEDIY--VASVDtgrgGARETLRIYDTAGlQGEQQQLPRHYLQFPDA 88
Cdd:smart00010   4 KLVVLGGGGVGKSALTIQFVQGHFVDEYD--PTIEDSYrkQIEID----GEVCLLDILDTAG-QEEFSAMRDQYMRTGEG 76

                           90       100       110
                   ....*....|....*....|....*....|....*....
gi 221330026    89 FVLVYDPMDPRSLDMLADIKADIEKHKEKKEIPVVVLAN 127
Cdd:smart00010  77 FLLVYSITDRQSFEEIAKFREQILRVKDRDDVPIVLVGN 115

Ral (Ras-like) family containing highly homologous RalA and RalB; The Ral (Ras-like) subfamily consists of the highly homologous RalA and RalB. Ral proteins are believed to play a crucial role in tumorigenesis, metastasis, endocytosis, and actin cytoskeleton dynamics. Despite their high sequence similarity (>80% sequence identity), nonoverlapping and opposing functions have been assigned to RalA and RalBs in tumor migration. In human bladder and prostate cancer cells, RalB promotes migration while RalA inhibits it. A Ral-specific set of GEFs has been identified that are activated by Ras binding. This RalGEF activity is enhanced by Ras binding to another of its target proteins, phosphatidylinositol 3-kinase (PI3K). Ral effectors include RLIP76/RalBP1, a Rac/cdc42 GAP, and the exocyst (Sec6/8) complex, a heterooctomeric protein complex that is involved in tethering vesicles to specific sites on the plasma membrane prior to exocytosis. In rat kidney cells, RalB is required for functional assembly of the exocyst and for localizing the exocyst to the leading edge of migrating cells. In human cancer cells, RalA is required to support anchorage-independent proliferation and RalB is required to suppress apoptosis. RalA has been shown to localize to the plasma membrane while RalB is localized to the intracellular vesicles. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221330026  11 KVLVCGMKGVGKTALIEQLVYGHVNPETElhPTIEDIY--VASVDtgrgGARETLRIYDTAGlQGEQQQLPRHYLQFPDA 88
Cdd:cd04139    2 KVIMVGSGGVGKSALTLQFMYDEFVEDYE--PTKADSYrkKVVLD----GEEVQLNILDTAG-QEDYAAIRDNYFRSGEG 74

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221330026  89 FVLVYDPMDPRSLDMLADIKADIEKHKEKKEIPVVVLANvraRAAPNPVEKV-MDRANIWCQRERIKHYTVNAMERPSLY 167
Cdd:cd04139   75 FLLVFSITDMESFTALAEFREQILRVKEDDNVPLLLVGN---KCDLEDKRQVsVEEAANLAEQWGVNYVETSAKTRANVD 151

                 ....*..
gi 221330026 168 EPFTTLC 174
Cdd:cd04139  152 KVFFDLV 158

Ras-related in brain (Rab) family of small guanosine triphosphatases (GTPases); Rab GTPases form the largest family within the Ras superfamily. There are at least 60 Rab genes in the human genome, and a number of Rab GTPases are conserved from yeast to humans. Rab GTPases are small, monomeric proteins that function as molecular switches to regulate vesicle trafficking pathways. The different Rab GTPases are localized to the cytosolic face of specific intracellular membranes, where they regulate distinct steps in membrane traffic pathways. In the GTP-bound form, Rab GTPases recruit specific sets of effector proteins onto membranes. Through their effectors, Rab GTPases regulate vesicle formation, actin- and tubulin-dependent vesicle movement, and membrane fusion. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which mask C-terminal lipid binding and promote cytosolic localization. While most unicellular organisms possess 5-20 Rab members, several have been found to possess 60 or more Rabs; for many of these Rab isoforms, homologous proteins are not found in other organisms. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Since crystal structures often lack C-terminal residues, the lipid modification site is not available for annotation in many of the CDs in the hierarchy, but is included where possible.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221330026  11 KVLVCGMKGVGKTALIEQLVYGHVNPETElhPTI-EDIYVASVDTgrGGARETLRIYDTAGlQGEQQQLPRHYLQFPDAF 89
Cdd:cd00154    2 KIVLIGDSGVGKTSLLLRFVDNKFSENYK--STIgVDFKSKTIEV--DGKKVKLQIWDTAG-QERFRSITSSYYRGAHGA 76

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221330026  90 VLVYDPMDPRSLDMLADIKADIEKHKEKKeIPVVVLAN----VRARAapnpVEKvmDRANIWCQRERIKHYTVNAMERPS 165
Cdd:cd00154   77 ILVYDVTNRESFENLDKWLNELKEYAPPN-IPIILVGNksdlEDERQ----VST--EEAQQFAKENGLLFFETSAKTGEN 149

                 ....*....
gi 221330026 166 LYEPFTTLC 174
Cdd:cd00154  150 VDEAFESLA 158

Ras-related and Estrogen-Regulated Growth inhibitor (RERG) and Ras-like 11 (RasL11)-like families; RERG (Ras-related and Estrogen- Regulated Growth inhibitor) and Ras-like 11 are members of a novel subfamily of Ras that were identified based on their behavior in breast and prostate tumors, respectively. RERG expression was decreased or lost in a significant fraction of primary human breast tumors that lack estrogen receptor and are correlated with poor clinical prognosis. Elevated RERG expression correlated with favorable patient outcome in a breast tumor subtype that is positive for estrogen receptor expression. In contrast to most Ras proteins, RERG overexpression inhibited the growth of breast tumor cells in vitro and in vivo. RasL11 was found to be ubiquitously expressed in human tissue, but down-regulated in prostate tumors. Both RERG and RasL11 lack the C-terminal CaaX prenylation motif, where a = an aliphatic amino acid and X = any amino acid, and are localized primarily in the cytoplasm. Both are believed to have tumor suppressor activity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221330026  11 KVLVCGMKGVGKTALIeqlvyghVNPET-----ELHPTIEDIYV--ASVDtgrgGARETLRIYDTAGLQGEQQ--QLPRH 81
Cdd:cd04146    1 KIAVLGASGVGKSALT-------VRFLTkrfigEYEPNLESLYSrqVTID----GEQVSLEIQDTPGQQQNEDpeSLERS 69

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 221330026  82 yLQFPDAFVLVYDPMDPRSLDMLADIKADI-EKHKEKKEIPVVVLAN 127
Cdd:cd04146   70 -LRWADGFVLVYSITDRSSFDVVSQLLQLIrEIKKRDGEIPVILVGN 115

Ras GTPase family containing H-Ras,N-Ras and K-Ras4A/4B; H-Ras/N-Ras/K-Ras subfamily. H-Ras, N-Ras, and K-Ras4A/4B are the prototypical members of the Ras family. These isoforms generate distinct signal outputs despite interacting with a common set of activators and effectors, and are strongly associated with oncogenic progression in tumor initiation. Mutated versions of Ras that are insensitive to GAP stimulation (and are therefore constitutively active) are found in a significant fraction of human cancers. Many Ras guanine nucleotide exchange factors (GEFs) have been identified. They are sequestered in the cytosol until activation by growth factors triggers recruitment to the plasma membrane or Golgi, where the GEF colocalizes with Ras. Active (GTP-bound) Ras interacts with several effector proteins that stimulate a variety of diverse cytoplasmic signaling activities. Some are known to positively mediate the oncogenic properties of Ras, including Raf, phosphatidylinositol 3-kinase (PI3K), RalGEFs, and Tiam1. Others are proposed to play negative regulatory roles in oncogenesis, including RASSF and NORE/MST1. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221330026  11 KVLVCGMKGVGKTALIEQLVYGHVNPETElhPTIEDIYVASVDTGrgGARETLRIYDTAGlQGEQQQLPRHYLQFPDAFV 90
Cdd:cd04138    3 KLVVVGAGGVGKSALTIQLIQNHFVDEYD--PTIEDSYRKQVVID--GETCLLDILDTAG-QEEYSAMRDQYMRTGEGFL 77

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 221330026  91 LVYDPMDPRSLDMLADIKADIEKHKEKKEIPVVVLAN 127
Cdd:cd04138   78 CVFAINSRKSFEDIHTYREQIKRVKDSDDVPMVLVGN 114

Ras Homolog Enriched in Brain (RheB) is a small GTPase; Rheb (Ras Homolog Enriched in Brain) subfamily. Rheb was initially identified in rat brain, where its expression is elevated by seizures or by long-term potentiation. It is expressed ubiquitously, with elevated levels in muscle and brain. Rheb functions as an important mediator between the tuberous sclerosis complex proteins, TSC1 and TSC2, and the mammalian target of rapamycin (TOR) kinase to stimulate cell growth. TOR kinase regulates cell growth by controlling nutrient availability, growth factors, and the energy status of the cell. TSC1 and TSC2 form a dimeric complex that has tumor suppressor activity, and TSC2 is a GTPase activating protein (GAP) for Rheb. The TSC1/TSC2 complex inhibits the activation of TOR kinase through Rheb. Rheb has also been shown to induce the formation of large cytoplasmic vacuoles in a process that is dependent on the GTPase cycle of Rheb, but independent of the TOR kinase, suggesting Rheb plays a role in endocytic trafficking that leads to cell growth and cell-cycle progression. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221330026  11 KVLVCGMKGVGKTALIEQLVYGHVnPETeLHPTIEDIYVASVDTgrGGARETLRIYDTAGlQGEQQQLPRHYLQFPDAFV 90
Cdd:cd04137    3 KIAVLGSRSVGKSSLTVQFVEGHF-VES-YYPTIENTFSKIITY--KGQEYHLEIVDTAG-QDEYSILPQKYSIGIHGYI 77

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 221330026  91 LVYDPMDPRSLDMLADIKADIEKHKEKKEIPVVVLAN 127
Cdd:cd04137   78 LVYSVTSRKSFEVVKVIYDKILDMLGKESVPIVLVGN 114

Rap-like family consists of Rap1, Rap2 and RSR1; The Rap subfamily consists of the Rap1, Rap2, and RSR1. Rap subfamily proteins perform different cellular functions, depending on the isoform and its subcellular localization. For example, in rat salivary gland, neutrophils, and platelets, Rap1 localizes to secretory granules and is believed to regulate exocytosis or the formation of secretory granules. Rap1 has also been shown to localize in the Golgi of rat fibroblasts, zymogen granules, plasma membrane, and microsomal membrane of the pancreatic acini, as well as in the endocytic compartment of skeletal muscle cells and fibroblasts. Rap1 localizes in the nucleus of human oropharyngeal squamous cell carcinomas (SCCs) and cell lines. Rap1 plays a role in phagocytosis by controlling the binding of adhesion receptors (typically integrins) to their ligands. In yeast, Rap1 has been implicated in multiple functions, including activation and silencing of transcription and maintenance of telomeres. Rap2 is involved in multiple functions, including activation of c-Jun N-terminal kinase (JNK) to regulate the actin cytoskeleton and activation of the Wnt/beta-catenin signaling pathway in embryonic Xenopus. A number of effector proteins for Rap2 have been identified, including isoform 3 of the human mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) and Traf2- and Nck-interacting kinase (TNIK), and the RalGEFs RalGDS, RGL, and Rlf, which also interact with Rap1 and Ras. RSR1 is the fungal homolog of Rap1 and Rap2. In budding yeasts, it is involved in selecting a site for bud growth, which directs the establishment of cell polarization. The Rho family GTPase Cdc42 and its GEF, Cdc24, then establish an axis of polarized growth. It is believed that Cdc42 interacts directly with RSR1 in vivo. In filamentous fungi such as Ashbya gossypii, RSR1 is a key regulator of polar growth in the hypha. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221330026  11 KVLVCGMKGVGKTALIEQLVYGhVNPETeLHPTIEDIYVASVDTGrgGARETLRIYDTAGLqgEQQQLPRH-YLQFPDAF 89
Cdd:cd04136    3 KLVVLGSGGVGKSALTVQFVQG-IFVDK-YDPTIEDSYRKQIEVD--CQQCMLEILDTAGT--EQFTAMRDlYIKNGQGF 76

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 221330026  90 VLVYDPMDPRSLDMLADIKADIEKHKEKKEIPVVVLAN 127
Cdd:cd04136   77 ALVYSITAQQSFNDLQDLREQILRVKDTEDVPMILVGN 114

Rab subfamily of small GTPases; Rab GTPases are implicated in vesicle trafficking.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221330026    11 KVLVCGMKGVGKTALIEQLVYGHVNPETElhPTIE-DIYVASVDtgRGGARETLRIYDTAGlQGEQQQLPRHYLQFPDAF 89
Cdd:smart00175   2 KIILIGDSGVGKSSLLSRFTDGKFSEQYK--STIGvDFKTKTIE--VDGKRVKLQIWDTAG-QERFRSITSSYYRGAVGA 76

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221330026    90 VLVYDPMDPRSLDMLADIKADIEKHKeKKEIPVVVLAN----VRARAapnpVEKvmDRANIWCQRERIKHYTVNAMERPS 165
Cdd:smart00175  77 LLVYDITNRESFENLENWLKELREYA-SPNVVIMLVGNksdlEEQRQ----VSR--EEAEAFAEEHGLPFFETSAKTNTN 149

                   ....*...
gi 221330026   166 LYEPFTTL 173
Cdd:smart00175 150 VEEAFEEL 157

Ras-related protein on chromosome 22 (RRP22) family; RRP22 (Ras-related protein on chromosome 22) subfamily consists of proteins that inhibit cell growth and promote caspase-independent cell death. Unlike most Ras proteins, RRP22 is down-regulated in many human tumor cells due to promoter methylation. RRP22 localizes to the nucleolus in a GTP-dependent manner, suggesting a novel function in modulating transport of nucleolar components. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Like most Ras family proteins, RRP22 is farnesylated.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221330026  11 KVLVCGMKGVGKTALIEQLVYGHVnPETELHPTIEDIYVASVDTgrGGARETLRIYDTAGLQ------GEQQQLPRHY-L 83
Cdd:cd04142    2 RVAVLGAPGVGKTAIVRQFLAQEF-PEEYIPTEHRRLYRPAVVL--SGRVYDLHILDVPNMQrypgtaGQEWMDPRFRgL 78

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|
gi 221330026  84 QFPDAFVLVYDPMDPRSLDMLADIKADI--EKHKEKKEIPVVVLANVRAR 131
Cdd:cd04142   79 RNSRAFILVYDICSPDSFHYVKLLRQQIleTRPAGNKEPPIVVVGNKRDQ 128

Rat sarcoma (Ras) family 2 of small guanosine triphosphatases (GTPases); The Ras2 subfamily, found exclusively in fungi, was first identified in Ustilago maydis. In U. maydis, Ras2 is regulated by Sql2, a protein that is homologous to GEFs (guanine nucleotide exchange factors) of the CDC25 family. Ras2 has been shown to induce filamentous growth, but the signaling cascade through which Ras2 and Sql2 regulate cell morphology is not known. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221330026  11 KVLVCGMKGVGKTALIEQLVYGHVNPETElhPTIEDIYVAS--VDtgrgGARETLRIYDTAGlQGEQQQLPRHYLQFPDA 88
Cdd:cd04144    1 KLVVLGDGGVGKTALTIQLCLNHFVETYD--PTIEDSYRKQvvVD----GQPCMLEVLDTAG-QEEYTALRDQWIREGEG 73

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 221330026  89 FVLVYDPMDPRSLDMLADIKADIEKHKEKKE--IPVVVLAN 127
Cdd:cd04144   74 FILVYSITSRSTFERVERFREQIQRVKDESAadVPIMIVGN 114

Rab GTPase family 30 (Rab30); Rab30 subfamily. Rab30 appears to be associated with the Golgi stack. It is expressed in a wide variety of tissue types and in humans maps to chromosome 11. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221330026  11 KVLVCGMKGVGKTALIEQLVYGHVNPETElhPTIE-DIYVASVDTGrgGARETLRIYDTAGlQGEQQQLPRHYLQFPDAF 89
Cdd:cd04114    9 KIVLIGNAGVGKTCLVRRFTQGLFPPGQG--ATIGvDFMIKTVEIK--GEKIKLQIWDTAG-QERFRSITQSYYRSANAL 83

                         90       100       110
                 ....*....|....*....|....*....|....*
gi 221330026  90 VLVYDPMDPRSLDMLADIKADIEKHKEKKEIPVVV 124
Cdd:cd04114   84 ILTYDITCEESFRCLPEWLREIEQYANNKVITILV 118

Ras homology family (Rho) of small guanosine triphosphatases (GTPases); Members of the Rho (Ras homology) family include RhoA, Cdc42, Rac, Rnd, Wrch1, RhoBTB, and Rop. There are 22 human Rho family members identified currently. These proteins are all involved in the reorganization of the actin cytoskeleton in response to external stimuli. They also have roles in cell transformation by Ras in cytokinesis, in focal adhesion formation and in the stimulation of stress-activated kinase. These various functions are controlled through distinct effector proteins and mediated through a GTP-binding/GTPase cycle involving three classes of regulating proteins: GAPs (GTPase-activating proteins), GEFs (guanine nucleotide exchange factors), and GDIs (guanine nucleotide dissociation inhibitors). Most Rho proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Rho proteins. Since crystal structures often lack C-terminal residues, this feature is not available for annotation in many of the CDs in the hierarchy.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221330026  11 KVLVCGMKGVGKTALIeqLVYGHVNPETELHPTIEDIYVASVDTgrGGARETLRIYDTAGlQGEQQQLPRHYLQFPDAFV 90
Cdd:cd00157    2 KIVVVGDGAVGKTCLL--ISYTTNKFPTEYVPTVFDNYSANVTV--DGKQVNLGLWDTAG-QEEYDRLRPLSYPQTDVFL 76

                         90
                 ....*....|..
gi 221330026  91 LVYDPMDPRSLD 102
Cdd:cd00157   77 LCFSVDSPSSFE 88

Rab GTPase family 33 includes Rab33A and Rab33B; Rab33B/Rab33A subfamily. Rab33B is ubiquitously expressed in mouse tissues and cells, where it is localized to the medial Golgi cisternae. It colocalizes with alpha-mannose II. Together with the other cisternal Rabs, Rab6A and Rab6A', it is believed to regulate the Golgi response to stress and is likely a molecular target in stress-activated signaling pathways. Rab33A (previously known as S10) is expressed primarily in the brain and immune system cells. In humans, it is located on the X chromosome at Xq26 and its expression is down-regulated in tuberculosis patients. Experimental evidence suggests that Rab33A is a novel CD8+ T cell factor that likely plays a role in tuberculosis disease processes. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221330026  11 KVLVCGMKGVGKTALIEQLVYGHVNPETElhPTIE-DIYVASVDTGrgGARETLRIYDTAGLQGEQQQLPRHYLQFPDAF 89
Cdd:cd04115    4 KIIVIGDSNVGKTCLTYRFCAGRFPERTE--ATIGvDFRERTVEID--GERIKVQLWDTAGQERFRKSMVQHYYRNVHAV 79

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 221330026  90 VLVYDPMDPRSLDMLADIKADIEKHKEKKEIPVVVLAN 127
Cdd:cd04115   80 VFVYDVTNMASFHSLPSWIEECEQHSLPNEVPRILVGN 117

YfjP GTPase; The Era (E. coli Ras-like protein)-like YfjP subfamily includes several uncharacterized bacterial GTPases that are similar to Era. They generally show sequence conservation in the region between the Walker A and B motifs (G1 and G3 box motifs), to the exclusion of other GTPases. Era is characterized by a distinct derivative of the KH domain (the pseudo-KH domain) which is located C-terminal to the GTPase domain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221330026  16 GMKGVGKTALIEQLVYGHVNPETELHPTIEDIYVASVDTGRGGaretLRIYDTAGLQGEQQ------QLPRHYLQFPDAF 89
Cdd:cd11383    4 GKTGAGKSSLCNALFGTEVAAVGDRRPTTRAAQAYVWQTGGDG----LVLLDLPGVGERGRrdreyeELYRRLLPEADLV 79

                 ....*....
gi 221330026  90 VLVYDPMDP 98
Cdd:cd11383   80 LWLLDADDR 88

Rho GTPase TC10 (Tc10); TC10 is a Rho family protein that has been shown to induce microspike formation and neurite outgrowth in vitro. Its expression changes dramatically after peripheral nerve injury, suggesting an important role in promoting axonal outgrowth and regeneration. TC10 regulates translocation of insulin-stimulated GLUT4 in adipocytes and has also been shown to bind directly to Golgi COPI coat proteins. GTP-bound TC10 in vitro can bind numerous potential effectors. Depending on its subcellular localization and distinct functional domains, TC10 can differentially regulate two types of filamentous actin in adipocytes. TC10 mRNAs are highly expressed in three types of mouse muscle tissues: leg skeletal muscle, cardiac muscle, and uterus; they were also present in brain, with higher levels in adults than in newborns. TC10 has also been shown to play a role in regulating the expression of cystic fibrosis transmembrane conductance regulator (CFTR) through interactions with CFTR-associated ligand (CAL). The GTP-bound form of TC10 directs the trafficking of CFTR from the juxtanuclear region to the secretory pathway toward the plasma membrane, away from CAL-mediated DFTR degradation in the lysosome. Most Rho proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Rho proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221330026  11 KVLVCGMKGVGKTALIeqLVYGHVNPETELHPTIEDIYVASVDTGrgGARETLRIYDTAGLQGEQQQLPrhyLQFP--DA 88
Cdd:cd04135    2 KCVVVGDGAVGKTCLL--MSYANDAFPEEYVPTVFDHYAVSVTVG--GKQYLLGLYDTAGQEDYDRLRP---LSYPmtDV 74

                         90
                 ....*....|..
gi 221330026  89 FVLVYDPMDPRS 100
Cdd:cd04135   75 FLICFSVVNPAS 86

Rab GTPase family 24 (Rab24); Rab24 is distinct from other Rabs in several ways. It exists primarily in the GTP-bound state, having a low intrinsic GTPase activity; it is not efficiently geranyl-geranylated at the C-terminus; it does not form a detectable complex with Rab GDP-dissociation inhibitors (GDIs); and it has recently been shown to undergo tyrosine phosphorylation when overexpressed in vitro. The specific function of Rab24 still remains unknown. It is found in a transport route between ER-cis-Golgi and late endocytic compartments. It is putatively involved in an autophagic pathway, possibly directing misfolded proteins in the ER to degradative pathways. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221330026  11 KVLVCGMKGVGKTALIEQLVYGH--VNPeteLHPTIEDIYVASVdTGRGGARETLRIYDTAGLQgEQQQLPRHYLQFPDA 88
Cdd:cd04118    2 KVVMLGKESVGKTSLVERYVHHRflVGP---YQNTIGAAFVAKR-MVVGERVVTLGIWDTAGSE-RYEAMSRIYYRGAKA 76

                         90
                 ....*....|..
gi 221330026  89 FVLVYDPMDPRS 100
Cdd:cd04118   77 AIVCYDLTDSSS 88

Signal recognition particle receptor, beta subunit (SR-beta), together with SR-alpha, forms the heterodimeric signal recognition particle (SRP); Signal recognition particle receptor, beta subunit (SR-beta). SR-beta and SR-alpha form the heterodimeric signal recognition particle (SRP or SR) receptor that binds SRP to regulate protein translocation across the ER membrane. Nascent polypeptide chains are synthesized with an N-terminal hydrophobic signal sequence that binds SRP54, a component of the SRP. SRP directs targeting of the ribosome-nascent chain complex (RNC) to the ER membrane via interaction with the SR, which is localized to the ER membrane. The RNC is then transferred to the protein-conducting channel, or translocon, which facilitates polypeptide translation across the ER membrane or integration into the ER membrane. SR-beta is found only in eukaryotes; it is believed to control the release of the signal sequence from SRP54 upon binding of the ribosome to the translocon. High expression of SR-beta has been observed in human colon cancer, suggesting it may play a role in the development of this type of cancer.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221330026  12 VLVCGMKGVGKTALIEQLVYGHVnPETelHPTIEDIYVASVDTGRGGARetLRIYDTAGLQGEQQQLPRHYLQFPDAFVL 91
Cdd:cd04105    3 VLLLGPSDSGKTALFTKLTTGKV-RST--VTSIEPNVASFYSNSSKGKK--LTLVDVPGHEKLRDKLLEYLKASLKAIVF 77

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 221330026  92 VYDPMD-PRSL----DMLADIKADIEKHKEKkeIPVVVLAN 127
Cdd:cd04105   78 VVDSATfQKNIrdvaEFLYDILTDLEKIKNK--IPILIACN 116

Sar1p-like members of the Ras-family of small GTPases; Yeast SAR1 is an essential gene required for transport of secretory proteins from the endoplasmic reticulum to the Golgi apparatus.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221330026     8 KVGKVLVCGMKGVGKTALIEQLVYGH-VNPETELHPTIEDIYVASVDtgrggaretlriYDTAGLQGEQQ--QLPRHYLQ 84
Cdd:smart00178  16 KHAKILFLGLDNAGKTTLLHMLKNDRlAQHQPTQHPTSEELAIGNIK------------FTTFDLGGHQQarRLWKDYFP 83

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*.
gi 221330026    85 FPDAFVLVYDPMDPRSLDmlaDIKADIE---KHKEKKEIPVVVLAN 127
Cdd:smart00178  84 EVNGIVYLVDAYDKERFA---ESKRELDallSDEELATVPFLILGN 126

Rab GTPase families 8, 10, 13 (Rab8, Rab10, Rab13); Rab8/Sec4/Ypt2 are known or suspected to be involved in post-Golgi transport to the plasma membrane. It is likely that these Rabs have functions that are specific to the mammalian lineage and have no orthologs in plants. Rab8 modulates polarized membrane transport through reorganization of actin and microtubules, induces the formation of new surface extensions, and has an important role in directed membrane transport to cell surfaces. The Ypt2 gene of the fission yeast Schizosaccharomyces pombe encodes a member of the Ypt/Rab family of small GTP-binding proteins, related in sequence to Sec4p of Saccharomyces cerevisiae but closer to mammalian Rab8. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221330026  11 KVLVCGMKGVGKTALIEQLVYGHVNPetELHPTIE-DIYVASVDTgrGGARETLRIYDTAGlQGEQQQLPRHYLQFPDAF 89
Cdd:cd01867    5 KLLLIGDSGVGKSCLLLRFSEDSFNP--SFISTIGiDFKIRTIEL--DGKKIKLQIWDTAG-QERFRTITTSYYRGAMGI 79

                         90       100
                 ....*....|....*....|....*
gi 221330026  90 VLVYDPMDPRSLDMLADIKADIEKH 114
Cdd:cd01867   80 ILVYDITDEKSFENIKNWMRNIDEH 104

Arf-like tumor suppressor gene 1 (ARLTS1 or Arl11); ARLTS1 (Arf-like tumor suppressor gene 1), also known as Arl11, is a member of the Arf family of small GTPases that is believed to play a major role in apoptotic signaling. ARLTS1 is widely expressed and functions as a tumor suppressor gene in several human cancers. ARLTS1 is a low-penetrance suppressor that accounts for a small percentage of familial melanoma or familial chronic lymphocytic leukemia (CLL). ARLTS1 inactivation seems to occur most frequently through biallelic down-regulation by hypermethylation of the promoter. In breast cancer, ARLTS1 alterations were typically a combination of a hypomorphic polymorphism plus loss of heterozygosity. In a case of thyroid adenoma, ARLTS1 alterations were polymorphism plus promoter hypermethylation. The nonsense polymorphism Trp149Stop occurs with significantly greater frequency in familial cancer cases than in sporadic cancer cases, and the Cys148Arg polymorphism is associated with an increase in high-risk familial breast cancer.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221330026  11 KVLVCGMKGVGKTALIEQLVyGHVNPETElhPTIeDIYVASVDTGRggaRETLRIYDTAGlQGEQQQLPRHYLQFPDAFV 90
Cdd:cd04156    1 QVLLLGLDSAGKSTLLYKLK-HAELVTTI--PTV-GFNVEMLQLEK---HLSLTVWDVGG-QEKMRTVWKCYLENTDGLV 72