P-loop containing Nucleoside Triphosphate Hydrolases; Members of the P-loop NTPase domain superfamily are characterized by a conserved nucleotide phosphate-binding motif, also referred to as the Walker A motif (GxxxxGK[S/T], where x is any residue), and the Walker B motif (hhhh[D/E], where h is a hydrophobic residue). The Walker A and B motifs bind the beta-gamma phosphate moiety of the bound nucleotide (typically ATP or GTP) and the Mg2+ cation, respectively. The P-loop NTPases are involved in diverse cellular functions, and they can be divided into two major structural classes: the KG (kinase-GTPase) class which includes Ras-like GTPases and its circularly permutated YlqF-like; and the ASCE (additional strand catalytic E) class which includes ATPase Binding Cassette (ABC), DExD/H-like helicases, 4Fe-4S iron sulfur cluster binding proteins of NifH family, RecA-like F1-ATPases, and ATPases Associated with a wide variety of Activities (AAA). Also included are a diverse set of nucleotide/nucleoside kinase families.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755497990   1 MNEVVHTSPTIGSNVEEIVVNNTRFLMWDIGGQESLRPSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRK 80
Cdd:cd04153   37 LGEVVHTSPTIGSNVEEIVYKNIRFLMWDIGGQESLRSSWNTYYTNTDAVILVIDSTDRERLPLTKEELYKMLAHEDLRK 116

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 755497990  81 AGLLIFANKQDVKECMTVAEISQFLKLTSIKDHQWHIQACCALTGEGLCQGLEWMMSR 138
Cdd:cd04153  117 AVLLVLANKQDLKGAMTPAEISESLGLTSIRDHTWHIQGCCALTGEGLPEGLDWIASR 174

Arf-like 5 (Arl5) and 8 (Arl8) GTPases; Arl5/Arl8 subfamily. Arl5 (Arf-like 5) and Arl8, like Arl4 and Arl7, are localized to the nucleus and nucleolus. Arl5 is developmentally regulated during embryogenesis in mice. Human Arl5 interacts with the heterochromatin protein 1-alpha (HP1alpha), a nonhistone chromosomal protein that is associated with heterochromatin and telomeres, and prevents telomere fusion. Arl5 may also play a role in embryonic nuclear dynamics and/or signaling cascades. Arl8 was identified from a fetal cartilage cDNA library. It is found in brain, heart, lung, cartilage, and kidney. No function has been assigned for Arl8 to date.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755497990   1 MNEVVHTSPTIGSNVEEIVVNNTRFLMWDIGGQESLRPSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRK 80
Cdd:cd04153   37 LGEVVHTSPTIGSNVEEIVYKNIRFLMWDIGGQESLRSSWNTYYTNTDAVILVIDSTDRERLPLTKEELYKMLAHEDLRK 116

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 755497990  81 AGLLIFANKQDVKECMTVAEISQFLKLTSIKDHQWHIQACCALTGEGLCQGLEWMMSR 138
Cdd:cd04153  117 AVLLVLANKQDLKGAMTPAEISESLGLTSIRDHTWHIQGCCALTGEGLPEGLDWIASR 174

ARF-like small GTPases; ARF, ADP-ribosylation factor; Ras homologues involved in vesicular transport. Activator of phospholipase D isoforms. Unlike Ras proteins they lack cysteine residues at their C-termini and therefore are unlikely to be prenylated. ARFs are N-terminally myristoylated. Contains ATP/GTP-binding motif (P-loop).

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755497990     1 MNEVVHTSPTIGSNVEEIVVNNTRFLMWDIGGQESLRPSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRK 80
Cdd:smart00177  35 LGESVTTIPTIGFNVETVTYKNISFTVWDVGGQDKIRPLWRHYYTNTQGLIFVVDSNDRDRIDEAREELHRMLNEDELRD 114

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 755497990    81 AGLLIFANKQDVKECMTVAEISQFLKLTSIKDHQWHIQACCALTGEGLCQGLEWMMSRLK 140
Cdd:smart00177 115 AVILVFANKQDLPDAMKAAEITEKLGLHSIRDRNWYIQPTCATSGDGLYEGLTWLSNNLK 174

GTPase SAR1 family domain [General function prediction only];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755497990   9 PTIGSNVEEIVV----NNTRFLMWDIGGQ---ESLRPSWNTYYTNTEFVIVVVDSTdrerISVTREELYKMLahEDLRKA 81
Cdd:COG1100   35 STNGVTIDKKELkldgLDVDLVIWDTPGQdefRETRQFYARQLTGASLYLFVVDGT----REETLQSLYELL--ESLRRL 108

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 755497990  82 G----LLIFANKQDvkeCMTVAEISQFLKLTSI--KDHQWHIQACCALTGEGL 128
Cdd:COG1100  109 GkkspIILVLNKID---LYDEEEIEDEERLKEAlsEDNIVEVVATSAKTGEGV 158

Arf-like 5 (Arl5) and 8 (Arl8) GTPases; Arl5/Arl8 subfamily. Arl5 (Arf-like 5) and Arl8, like Arl4 and Arl7, are localized to the nucleus and nucleolus. Arl5 is developmentally regulated during embryogenesis in mice. Human Arl5 interacts with the heterochromatin protein 1-alpha (HP1alpha), a nonhistone chromosomal protein that is associated with heterochromatin and telomeres, and prevents telomere fusion. Arl5 may also play a role in embryonic nuclear dynamics and/or signaling cascades. Arl8 was identified from a fetal cartilage cDNA library. It is found in brain, heart, lung, cartilage, and kidney. No function has been assigned for Arl8 to date.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755497990   1 MNEVVHTSPTIGSNVEEIVVNNTRFLMWDIGGQESLRPSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRK 80
Cdd:cd04153   37 LGEVVHTSPTIGSNVEEIVYKNIRFLMWDIGGQESLRSSWNTYYTNTDAVILVIDSTDRERLPLTKEELYKMLAHEDLRK 116

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 755497990  81 AGLLIFANKQDVKECMTVAEISQFLKLTSIKDHQWHIQACCALTGEGLCQGLEWMMSR 138
Cdd:cd04153  117 AVLLVLANKQDLKGAMTPAEISESLGLTSIRDHTWHIQGCCALTGEGLPEGLDWIASR 174

ADP-ribosylation factor family; Pfam combines a number of different Prosite families together

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755497990    1 MNEVVHTSPTIGSNVEEIVVNNTRFLMWDIGGQESLRPSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRK 80
Cdd:pfam00025  22 LGEIVTTIPTIGFNVETVTYKNVKFTVWDVGGQESLRPLWRNYFPNTDAVIFVVDSADRDRIEEAKEELHALLNEEELAD 101

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 755497990   81 AGLLIFANKQDVKECMTVAEISQFLKLTSIKDHQWHIQACCALTGEGLCQGLEWM 135
Cdd:pfam00025 102 APLLILANKQDLPGAMSEAEIRELLGLHELKDRPWEIQGCSAVTGEGLDEGLDWL 156

ARF-like small GTPases; ARF, ADP-ribosylation factor; Ras homologues involved in vesicular transport. Activator of phospholipase D isoforms. Unlike Ras proteins they lack cysteine residues at their C-termini and therefore are unlikely to be prenylated. ARFs are N-terminally myristoylated. Contains ATP/GTP-binding motif (P-loop).

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755497990     1 MNEVVHTSPTIGSNVEEIVVNNTRFLMWDIGGQESLRPSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRK 80
Cdd:smart00177  35 LGESVTTIPTIGFNVETVTYKNISFTVWDVGGQDKIRPLWRHYYTNTQGLIFVVDSNDRDRIDEAREELHRMLNEDELRD 114

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 755497990    81 AGLLIFANKQDVKECMTVAEISQFLKLTSIKDHQWHIQACCALTGEGLCQGLEWMMSRLK 140
Cdd:smart00177 115 AVILVFANKQDLPDAMKAAEITEKLGLHSIRDRNWYIQPTCATSGDGLYEGLTWLSNNLK 174

ADP-ribosylation factor-1 (Arf1) and ADP-ribosylation factor-5 (Arf5); The Arf1-Arf5-like subfamily contains Arf1, Arf2, Arf3, Arf4, Arf5, and related proteins. Arfs1-5 are soluble proteins that are crucial for assembling coat proteins during vesicle formation. Each contains an N-terminal myristoylated amphipathic helix that is folded into the protein in the GDP-bound state. GDP/GTP exchange exposes the helix, which anchors to the membrane. Following GTP hydrolysis, the helix dissociates from the membrane and folds back into the protein. A general feature of Arf1-5 signaling may be the cooperation of two Arfs at the same site. Arfs1-5 are generally considered to be interchangeable in function and location, but some specific functions have been assigned. Arf1 localizes to the early/cis-Golgi, where it is activated by GBF1 and recruits the coat protein COPI. It also localizes to the trans-Golgi network (TGN), where it is activated by BIG1/BIG2 and recruits the AP1, AP3, AP4, and GGA proteins. Humans, but not rodents and other lower eukaryotes, lack Arf2. Human Arf3 shares 96% sequence identity with Arf1 and is believed to generally function interchangeably with Arf1. Human Arf4 in the activated (GTP-bound) state has been shown to interact with the cytoplasmic domain of epidermal growth factor receptor (EGFR) and mediate the EGF-dependent activation of phospholipase D2 (PLD2), leading to activation of the activator protein 1 (AP-1) transcription factor. Arf4 has also been shown to recognize the C-terminal sorting signal of rhodopsin and regulate its incorporation into specialized post-Golgi rhodopsin transport carriers (RTCs). There is some evidence that Arf5 functions at the early-Golgi and the trans-Golgi to affect Golgi-associated alpha-adaptin homology Arf-binding proteins (GGAs).

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755497990   3 EVVHTSPTIGSNVEEIVVNNTRFLMWDIGGQESLRPSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRKAG 82
Cdd:cd04150   24 EIVTTIPTIGFNVETVEYKNISFTVWDVGGQDKIRPLWRHYFQNTQGLIFVVDSNDRERIGEAREELQRMLNEDELRDAV 103

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 755497990  83 LLIFANKQDVKECMTVAEISQFLKLTSIKDHQWHIQACCALTGEGLCQGLEWM 135
Cdd:cd04150  104 LLVFANKQDLPNAMSAAEVTDKLGLHSLRNRNWYIQATCATSGDGLYEGLDWL 156

Arf-like 3 (Arl3) GTPase; Arl3 (Arf-like 3) is an Arf family protein that differs from most Arf family members in the N-terminal extension. In is inactive, GDP-bound form, the N-terminal extension forms an elongated loop that is hydrophobically anchored into the membrane surface; however, it has been proposed that this region might form a helix in the GTP-bound form. The delta subunit of the rod-specific cyclic GMP phosphodiesterase type 6 (PDEdelta) is an Arl3 effector. Arl3 binds microtubules in a regulated manner to alter specific aspects of cytokinesis via interactions with retinitis pigmentosa 2 (RP2). It has been proposed that RP2 functions in concert with Arl3 to link the cell membrane and the cytoskeleton in photoreceptors as part of the cell signaling or vesicular transport machinery. In mice, the absence of Arl3 is associated with abnormal epithelial cell proliferation and cyst formation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755497990   3 EVVHTSPTIGSNVEEIVVNNTRFLMWDIGGQESLRPSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRKAG 82
Cdd:cd04155   39 DISHITPTQGFNIKNVQADGFKLNVWDIGGQRKIRPYWRNYFENTDVLIYVIDSADRKRFEEAGQELVELLEEEKLAGVP 118

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|..
gi 755497990  83 LLIFANKQDVKECMTVAEISQFLKLTSIKDHQWHIQACCALTGEGLCQGLEW 134
Cdd:cd04155  119 VLVFANKQDLLTAAPAEEVAEALNLHDIRDRSWHIQACSAKTGEGLQEGMNW 170

ADP ribosylation factor 6 (Arf6); Arf6 subfamily. Arf6 (ADP ribosylation factor 6) proteins localize to the plasma membrane, where they perform a wide variety of functions. In its active, GTP-bound form, Arf6 is involved in cell spreading, Rac-induced formation of plasma membrane ruffles, cell migration, wound healing, and Fc-mediated phagocytosis. Arf6 appears to change the actin structure at the plasma membrane by activating Rac, a Rho family protein involved in membrane ruffling. Arf6 is required for and enhances Rac formation of ruffles. Arf6 can regulate dendritic branching in hippocampal neurons, and in yeast it localizes to the growing bud, where it plays a role in polarized growth and bud site selection. In leukocytes, Arf6 is required for chemokine-stimulated migration across endothelial cells. Arf6 also plays a role in down-regulation of beta2-adrenergic receptors and luteinizing hormone receptors by facilitating the release of sequestered arrestin to allow endocytosis. Arf6 is believed to function at multiple sites on the plasma membrane through interaction with a specific set of GEFs, GAPs, and effectors. Arf6 has been implicated in breast cancer and melanoma cell invasion, and in actin remodelling at the invasion site of Chlamydia infection.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755497990   1 MNEVVHTSPTIGSNVEEIVVNNTRFLMWDIGGQESLRPSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRK 80
Cdd:cd04149   31 LGQSVTTIPTVGFNVETVTYKNVKFNVWDVGGQDKIRPLWRHYYTGTQGLIFVVDSADRDRIDEARQELHRIINDREMRD 110

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 755497990  81 AGLLIFANKQDVKECMTVAEISQFLKLTSIKDHQWHIQACCALTGEGLCQGLEWM 135
Cdd:cd04149  111 ALLLVFANKQDLPDAMKPHEIQEKLGLTRIRDRNWYVQPSCATSGDGLYEGLTWL 165

Arf-like 6 (Arl6) GTPase; Arl6 (Arf-like 6) forms a subfamily of the Arf family of small GTPases. Arl6 expression is limited to the brain and kidney in adult mice, but it is expressed in the neural plate and somites during embryogenesis, suggesting a possible role for Arl6 in early development. Arl6 is also believed to have a role in cilia or flagella function. Several proteins have been identified that bind Arl6, including Arl6 interacting protein (Arl6ip), and SEC61beta, a subunit of the heterotrimeric conducting channel SEC61p. Based on Arl6 binding to these effectors, Arl6 is also proposed to play a role in protein transport, membrane trafficking, or cell signaling during hematopoietic maturation. At least three specific homozygous Arl6 mutations in humans have been found to cause Bardet-Biedl syndrome, a disorder characterized by obesity, retinopathy, polydactyly, renal and cardiac malformations, learning disabilities, and hypogenitalism. Older literature suggests that Arl6 is a part of the Arl4/Arl7 subfamily, but analyses based on more recent sequence data place Arl6 in its own subfamily.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755497990   6 HTSPTIGSNVEEIVVNNTRFLMWDIGGQESLRPSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDL--RKAGL 83
Cdd:cd04157   28 NIVPTVGFNVESFKKGNLSFTAFDMSGQGKYRGLWEHYYKNIQGIIFVIDSSDRLRMVVAKDELELLLNHPDIkhRRIPI 107

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|..
gi 755497990  84 LIFANKQDVKECMTVAEISQFLKLTSIKDHQWHIQACCALTGEGLCQGLEWM 135
Cdd:cd04157  108 LFYANKMDLPDALTAVKITQLLCLENIKDKPWHIFASSALTGEGLDEGVDWL 159

(ADP-ribosylation factor domain protein 1 (ARD1); ARD1 (ADP-ribosylation factor domain protein 1) is an unusual member of the Arf family. In addition to the C-terminal Arf domain, ARD1 has an additional 46-kDa N-terminal domain that contains a RING finger domain, two predicted B-Boxes, and a coiled-coil protein interaction motif. This domain belongs to the TRIM (tripartite motif) or RBCC (RING, B-Box, coiled-coil) family. Like most Arfs, the ARD1 Arf domain lacks detectable GTPase activity. However, unlike most Arfs, the full-length ARD1 protein has significant GTPase activity due to the GAP (GTPase-activating protein) activity exhibited by the 46-kDa N-terminal domain. The GAP domain of ARD1 is specific for its own Arf domain and does not bind other Arfs. The rate of GDP dissociation from the ARD1 Arf domain is slowed by the adjacent 15 amino acids, which act as a GDI (GDP-dissociation inhibitor) domain. ARD1 is ubiquitously expressed in cells and localizes to the Golgi and to the lysosomal membrane. Two Tyr-based motifs in the Arf domain are responsible for Golgi localization, while the GAP domain controls lysosomal localization.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755497990   2 NEVVHTSPTIGSNVEEIVVNNTRFLMWDIGGQESLRPSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRKA 81
Cdd:cd04158   22 DEFMQPIPTIGFNVETVEYKNLKFTIWDVGGKHKLRPLWKHYYLNTQAVVFVIDSSHRDRVSEAHSELAKLLTEKELRDA 101

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 755497990  82 GLLIFANKQDVKECMTVAEISQFLKLTSI-KDHQWHIQACCALTGEGLCQGLEWMMSRL 139
Cdd:cd04158  102 LLLIFANKQDVAGALSVEEMTELLSLHKLcCGRSWYIQGCDARSGMGLYEGLDWLSRQL 160

Arf-like 9 (Arl9) and 10 (Arl10) GTPases; Arl10-like subfamily. Arl9/Arl10 was identified from a human cancer-derived EST dataset. No functional information about the subfamily is available at the current time, but crystal structures of human Arl10b and Arl10c have been solved.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755497990   4 VVHTSPTIGSNVEEIVVNNTRFLMWDIGGQESLRPSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRKAGL 83
Cdd:cd04159   25 SEDTIPTVGFNMRKVTKGNVTIKVWDLGGQPRFRSMWERYCRGVNAIVYVVDAADREKLEVAKNELHDLLEKPSLEGIPL 104

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 755497990  84 LIFANKQDVKECMTVAEISQFLKLTSIKDHQWhiqaCC----ALTGEGLCQGLEWMMSR 138
Cdd:cd04159  105 LVLGNKNDLPGALSVDELIEQMNLKSITDREV----SCysisAKEKTNIDIVLDWLIKH 159

Sar1 is an essential component of COPII vesicle coats; Sar1 is an essential component of COPII vesicle coats involved in export of cargo from the ER. The GTPase activity of Sar1 functions as a molecular switch to control protein-protein and protein-lipid interactions that direct vesicle budding from the ER. Activation of the GDP to the GTP-bound form of Sar1 involves the membrane-associated guanine nucleotide exchange factor (GEF) Sec12. Sar1 is unlike all Ras superfamily GTPases that use either myristoyl or prenyl groups to direct membrane association and function, in that Sar1 lacks such modification. Instead, Sar1 contains a unique nine-amino-acid N-terminal extension. This extension contains an evolutionarily conserved cluster of bulky hydrophobic amino acids, referred to as the Sar1-N-terminal activation recruitment (STAR) motif. The STAR motif mediates the recruitment of Sar1 to ER membranes and facilitates its interaction with mammalian Sec12 GEF leading to activation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755497990   2 NEVVHTSPTIGSNVEEIVVNNTRFLMWDIGGQESLRPSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRKA 81
Cdd:cd00879   42 DRLAQHVPTLHPTSEELTIGNVKFTTFDLGGHEQARRVWKDYFPEVDGIVFLVDAADPERFQESKEELDSLLNDEELANV 121

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 755497990  82 GLLIFANKQDVKECMTVAEISQFLKLT---------SIKDHQWHIQA---CCALTGEGLCQGLEWM 135
Cdd:cd00879  122 PILILGNKIDKPGAVSEEELREALGLYgtttgkggvSLKVSNIRPVEvfmCSVVKRQGYGEGFRWL 187

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 755497990     9 PTIGSNVEEIVVNNTRFLMWDIGGQESLRPSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRKAGLLIFAN 88
Cdd:smart00178  47 PTQHPTSEELAIGNIKFTTFDLGGHQQARRLWKDYFPEVNGIVYLVDAYDKERFAESKRELDALLSDEELATVPFLILGN 126

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....
gi 755497990    89 KQDVKECMTVAEISQFLKLTSIKDHQWHIQA-------CCALTGEGLCQGLEWM 135
Cdd:smart00178 127 KIDAPYAASEDELRYALGLTNTTTGKGKVGVrpvevfmCSVVRRMGYGEGFKWL 180

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 755497990   6 HTSPTIGSN--VEEIVVNNTRFLM--WDIGGQE---SLRPSwntYYTNTEFVIVVVDSTDRErisvTREELYKMLahEDL 78
Cdd:cd00154   28 NYKSTIGVDfkSKTIEVDGKKVKLqiWDTAGQErfrSITSS---YYRGAHGAILVYDVTNRE----SFENLDKWL--NEL 98

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 755497990  79 RKAG-----LLIFANKQDVKECMTV--AEISQFlkltsIKDHQWHIQACCALTGEG 127
Cdd:cd00154   99 KEYAppnipIILVGNKSDLEDERQVstEEAQQF-----AKENGLLFFETSAKTGEN 149

Rab family protein; Provisional

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 755497990   8 SPTIGSN--VEEIVVNNTRF--LMWDIGGQESLRPSWNTYYTNTEFVIVVVDSTDRE 60
Cdd:PLN03118  43 APTIGVDfkIKQLTVGGKRLklTIWDTAGQERFRTLTSSYYRNAQGIILVYDVTRRE 99

G-protein alpha subunit; G proteins couple receptors of extracellular signals to intracellular signaling pathways. The G protein alpha subunit binds guanyl nucleotide and is a weak GTPase. A set of residues that are unique to G-alpha as compared to its ancestor the Arf-like family form a ring of residues centered on the nucleotide binding site. A Ggamma is found fused to an inactive Galpha in the Dictyostelium protein gbqA.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755497990    4 VVHTS-PTIGSNVEEIVVNNTRFLMWDIGGQESLRPSWNTYYTNTEFVIVVV-----DSTDRERISVTR-EE---LYK-M 72
Cdd:pfam00503 147 ILRARvKTTGIIETKFEFKGLKFRLFDVGGQRSERKKWIHCFEDVTAIIFVVslseyDQVLYEDDSTNRmEEslkLFEeI 226

                          90       100
                  ....*....|....*....|
gi 755497990   73 LAHEDLRKAGLLIFANKQDV 92
Cdd:pfam00503 227 CNSPWFKNTPIILFLNKKDL 246

Rab GTPase family 35 (Rab35); Rab35 is one of several Rab proteins to be found to participate in the regulation of osteoclast cells in rats. In addition, Rab35 has been identified as a protein that interacts with nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) in human cells. Overexpression of NPM-ALK is a key oncogenic event in some anaplastic large-cell lymphomas; since Rab35 interacts with N|PM-ALK, it may provide a target for cancer treatments. 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 755497990  10 TIGSN--VEEIVVNNTR--FLMWDIGGQESLRPSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRKAGLLi 85
Cdd:cd04110   38 TIGVDfkIRTVEINGERvkLQIWDTAGQERFRTITSTYYRGTHGVIVVYDVTNGESFVNVKRWLQEIEQNCDDVCKVLV- 116

                 ....*.
gi 755497990  86 fANKQD 91
Cdd:cd04110  117 -GNKND 121

Rab GTPase family 12 (Rab12); Rab12 was first identified in canine cells, where it was localized to the Golgi complex. The specific function of Rab12 remains unknown, and inconsistent results about its cellular localization have been reported. More recent studies have identified Rab12 associated with post-Golgi vesicles, or with other small vesicle-like structures but not with the Golgi complex. 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. 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 755497990  24 RFLMWDIGGQESLRPSWNTYYTNTEFVIVVVDSTDRErisvTREELYKML------AHEDlrkAGLLIFANKQDvkeCMT 97
Cdd:cd04120   50 RLQIWDTAGQERFNSITSAYYRSAKGIILVYDITKKE----TFDDLPKWMkmidkyASED---AELLLVGNKLD---CET 119

                 ....*.
gi 755497990  98 VAEISQ 103
Cdd:cd04120  120 DREITR 125

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 755497990  29 DIGGQESLRPSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRKAGLLIFANKQDV--KECMTVAEISQFLk 106
Cdd:cd04139   54 DTAGQEDYAAIRDNYFRSGEGFLLVFSITDMESFTALAEFREQILRVKEDDNVPLLLVGNKCDLedKRQVSVEEAANLA- 132

                         90
                 ....*....|..
gi 755497990 107 ltsikdHQWHIQ 118
Cdd:cd04139  133 ------EQWGVN 138

Ras family; Includes sub-families Ras, Rab, Rac, Ral, Ran, Rap Ypt1 and more. Shares P-loop motif with GTP_EFTU, arf and myosin_head. See pfam00009 pfam00025, pfam00063. As regards Rab GTPases, these are important regulators of vesicle formation, motility and fusion. They share a fold in common with all Ras GTPases: this is a six-stranded beta-sheet surrounded by five alpha-helices.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755497990    9 PTIG--SNVEEIVVNNTRFLM--WDIGGQE---SLRPSwntYYTNTEFVIVVVDSTDR---ERISVTREELykmlahedL 78
Cdd:pfam00071  30 PTIGvdFYTKTIEVDGKTVKLqiWDTAGQErfrALRPL---YYRGADGFLLVYDITSRdsfENVKKWVEEI--------L 98

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 755497990   79 RKAG----LLIFANKQDVKE--CMTVAEISQFLKltsikdhQWHIQ--ACCALTGEG 127
Cdd:pfam00071  99 RHADenvpIVLVGNKCDLEDqrVVSTEEGEALAK-------ELGLPfmETSAKTNEN 148

Rab GTPase family 18 (Rab18); Rab18 subfamily. Mammalian Rab18 is implicated in endocytic transport and is expressed most highly in polarized epithelial cells. However, trypanosomal Rab, TbRAB18, is upregulated in the BSF (Blood Stream Form) stage and localized predominantly to elements of the Golgi complex. In human and mouse cells, Rab18 has been identified in lipid droplets, organelles that store neutral lipids. 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 755497990   7 TSPTIGSN--VEEIVVNNTRF--LMWDIGGQESLRPSWNTYYTNTEFVIVVVDSTDRE---RISVTREELYKMLAHEDLR 79
Cdd:cd01863   29 LSSTIGVDfkVKTVTVDGKKVklAIWDTAGQERFRTLTSSYYRGAQGVILVYDVTRRDtfdNLDTWLNELDTYSTNPDAV 108

                         90
                 ....*....|....*....
gi 755497990  80 KaglLIFANKQDvKECMTV 98
Cdd:cd01863  109 K---MLVGNKID-KENREV 123

Rab family protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755497990  27 MWDIGGQESLRPSWNTYYTNTEFVIVVVDstdrerisVTREELYKMLAH--EDLRKAG-----LLIFANKQDV--KECMT 97
Cdd:PLN03108  59 IWDTAGQESFRSITRSYYRGAAGALLVYD--------ITRRETFNHLASwlEDARQHAnanmtIMLIGNKCDLahRRAVS 130

                 ....*....
gi 755497990  98 VAEISQFLK 106
Cdd:PLN03108 131 TEEGEQFAK 139

Rab GTPase family 1 includes the yeast homolog Ypt1; Rab1/Ypt1 subfamily. Rab1 is found in every eukaryote and is a key regulatory component for the transport of vesicles from the ER to the Golgi apparatus. Studies on mutations of Ypt1, the yeast homolog of Rab1, showed that this protein is necessary for the budding of vesicles of the ER as well as for their transport to, and fusion with, the Golgi apparatus. 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 755497990  27 MWDIGGQESLRPSWNTYYTNTEFVIVVVDSTDRERISVTREELYKM--LAHEDLRKaglLIFANKQDV--KECMTVAEIS 102
Cdd:cd01869   55 IWDTAGQERFRTITSSYYRGAHGIIIVYDVTDQESFNNVKQWLQEIdrYASENVNK---LLVGNKCDLtdKKVVDYTEAK 131

                 ....*...
gi 755497990 103 QFLKLTSI 110
Cdd:cd01869  132 EFADELGI 139

Rab-related GTPase family includes Rab5 and Rab22; regulates early endosome fusion; The Rab5-related subfamily includes Rab5 and Rab22 of mammals, Ypt51/Ypt52/Ypt53 of yeast, and RabF of plants. The members of this subfamily are involved in endocytosis and endocytic-sorting pathways. In mammals, Rab5 GTPases localize to early endosomes and regulate fusion of clathrin-coated vesicles to early endosomes and fusion between early endosomes. In yeast, Ypt51p family members similarly regulate membrane trafficking through prevacuolar compartments. 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 755497990   7 TSPTIGS--NVEEIVVNNT--RFLMWDIGGQE---SLRPswnTYYTNTEFVIVVVDstdrerisVTREELYKMLAH--ED 77
Cdd:cd01860   30 QESTIGAafLTQTVNLDDTtvKFEIWDTAGQEryrSLAP---MYYRGAAAAIVVYD--------ITSEESFEKAKSwvKE 98

                         90       100       110
                 ....*....|....*....|....*....|....
gi 755497990  78 LRKAG---LLIF--ANKQDV--KECMTVAEISQF 104
Cdd:cd01860   99 LQEHGppnIVIAlaGNKADLesKRQVSTEEAQEY 132

Ras-related nuclear proteins (Ran)/TC4 family of small GTPases; Ran GTPase is involved in diverse biological functions, such as nuclear transport, spindle formation during mitosis, DNA replication, and cell division. Among the Ras superfamily, Ran is a unique small G protein. It does not have a lipid modification motif at the C-terminus to bind to the membrane, which is often observed within the Ras superfamily. Ran may therefore interact with a wide range of proteins in various intracellular locations. Like other GTPases, Ran exists in GTP- and GDP-bound conformations that interact differently with effectors. Conversion between these forms and the assembly or disassembly of effector complexes requires the interaction of regulator proteins. The intrinsic GTPase activity of Ran is very low, but it is greatly stimulated by a GTPase-activating protein (RanGAP1) located in the cytoplasm. By contrast, RCC1, a guanine nucleotide exchange factor that generates RanGTP, is bound to chromatin and confined to the nucleus. Ran itself is mobile and is actively imported into the nucleus by a mechanism involving NTF-2. Together with the compartmentalization of its regulators, this is thought to produce a relatively high concentration of RanGTP in the nucleus.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755497990   9 PTIGSNVEEIVVNNT----RFLMWDIGGQE---SLRpswNTYYTNTEFVIVVVDSTDRerisVTreelYKMLA--HEDL- 78
Cdd:cd00877   31 ATLGVEVHPLDFHTNrgkiRFNVWDTAGQEkfgGLR---DGYYIQGQCAIIMFDVTSR----VT----YKNVPnwHRDLv 99