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 15208641 406 RVVTLGLDGAGKTTILFKLKQDEFMQPIPTIGFNVETVEYKNLKFTIWDVGGKHKLRPLWKHYYLNTQAVVFVVDSSHRD 485
Cdd:cd04158   1 RVVTLGLDGAGKTTILFKLKQDEFMQPIPTIGFNVETVEYKNLKFTIWDVGGKHKLRPLWKHYYLNTQAVVFVIDSSHRD 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 15208641 486 RISEAHSELAKLLTEKELRDALLLIFANKQDVAGALSVEEITELLSLHKLCCGRSWYIQGCDARS 550
Cdd:cd04158  81 RVSEAHSELAKLLTEKELRDALLLIFANKQDVAGALSVEEMTELLSLHKLCCGRSWYIQGCDARS 145

Modified RING finger, HC subclass (C3HC3D-type), found in tripartite motif-containing protein 23 (TRIM23) and similar proteins; TRIM23, also known as ADP-ribosylation factor domain-containing protein 1, GTP-binding protein ARD-1, or RING finger protein 46 (RNF46), is an E3 ubiquitin-protein ligase belonging to the C-IX subclass of the TRIM (tripartite motif) family of proteins that are defined by an N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a modified C3HC3D-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as C-terminal ADP ribosylation factor (ARF) domains. TRIM23 is involved in nuclear factor (NF)-kappaB activation. It mediates atypical lysine 27 (K27)-linked polyubiquitin conjugation to NF-kappaB essential modulator NEMO, also known as IKKgamma, which plays an important role in the NF-kappaB pathway, and this conjugation is essential for TLR3- and RIG-I/MDA5-mediated antiviral innate and inflammatory responses. It also regulates adipocyte differentiation via stabilization of the adipogenic activator peroxisome proliferator-activated receptor gamma (PPARgamma) through atypical ubiquitin conjugation to PPARgamma. Moreover, TRIM23 interacts with and polyubiquitinates yellow fever virus (YFV) NS5 to promote its binding to STAT2 and trigger type I interferon (IFN-I) signaling inhibition.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 15208641  28 VLECGVCEDVFSLQGDKVPRLLLCGHTVCHDCLTRLPLHGRAIRCPFDRQ 77
Cdd:cd16645   1 VLECGVCEDVFSLQGDKVPRLLLCGHTVCHDCLTRLPLHGRAVRCPFDRQ 50

second B-box-type 2 zinc finger found in tripartite motif-containing protein 23 (TRIM23) and similar proteins; TRIM23, also known as ADP-ribosylation factor domain-containing protein 1, GTP-binding protein ARD-1, or RING finger protein 46 (RNF46), is an E3 ubiquitin-protein ligase belonging to the C-IX subclass of TRIM (tripartite motif) family of proteins that are defined by an N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a RING finger, two Bbox2, and a coiled coil region, as well as C-terminal ADP ribosylation factor (ARF) domains. The type 2 B-box (Bbox2) zinc finger is characterized by a CHC3H2 zinc-binding consensus motif. TRIM23 is involved in nuclear factor (NF)-kappaB activation. It mediates atypical lysine 27 (K27)-linked polyubiquitin conjugation to NF-kappaB essential modulator NEMO, also known as IKKgamma, which plays an important role in the NF-kappaB pathway, and this conjugation is essential for TLR3- and RIG-I/MDA5-mediated antiviral innate and inflammatory responses. It also regulates adipocyte differentiation via stabilization of the adipogenic activator peroxisome proliferator-activated receptor gamma (PPARgamma) through atypical ubiquitin conjugation to PPARgamma. Moreover, TRIM23 interacts with and polyubiquitinates yellow fever virus (YFV) NS5 to promote its binding to STAT2 and trigger type I interferon (IFN-I) signaling inhibition.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 15208641 174 EKTMCSQHQVHAIEFVCLEEGCQTSPLMCCVCKEYGKHQGHKHSVLEPEA 223
Cdd:cd19774   1 EKPKCPIHPDHLIEFVCLEEDCQESPLMCIICKEYGKHQGHKHELLEEEA 50

(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 15208641 406 RVVTLGLDGAGKTTILFKLKQDEFMQPIPTIGFNVETVEYKNLKFTIWDVGGKHKLRPLWKHYYLNTQAVVFVVDSSHRD 485
Cdd:cd04158   1 RVVTLGLDGAGKTTILFKLKQDEFMQPIPTIGFNVETVEYKNLKFTIWDVGGKHKLRPLWKHYYLNTQAVVFVIDSSHRD 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 15208641 486 RISEAHSELAKLLTEKELRDALLLIFANKQDVAGALSVEEITELLSLHKLCCGRSWYIQGCDARS 550
Cdd:cd04158  81 RVSEAHSELAKLLTEKELRDALLLIFANKQDVAGALSVEEMTELLSLHKLCCGRSWYIQGCDARS 145

ADP-ribosylation factor; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15208641  402 KMEIRVVTLGLDGAGKTTILFKLKQDEFMQPIPTIGFNVETVEYKNLKFTIWDVGGKHKLRPLWKHYYLNTQAVVFVVDS 481
Cdd:PTZ00133  15 KKEVRILMVGLDAAGKTTILYKLKLGEVVTTIPTIGFNVETVEYKNLKFTMWDVGGQDKLRPLWRHYYQNTNGLIFVVDS 94

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 15208641  482 SHRDRISEAHSELAKLLTEKELRDALLLIFANKQDVAGALSVEEITELLSLHKLcCGRSWYIQGCDARS 550
Cdd:PTZ00133  95 NDRERIGDAREELERMLSEDELRDAVLLVFANKQDLPNAMSTTEVTEKLGLHSV-RQRNWYIQGCCATT 162

B-Box C-terminal domain; Coiled coil region C-terminal to (some) B-Box domains

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15208641    226 IRASILDMAHCIRTFTEEISDYSRKLVGIVQHIEGgeqivedgigmahtehvpgTAENARSCIRAYFYDLHETLCRQEEM 305
Cdd:smart00502   1 QREALEELLTKLRKKAAELEDALKQLISIIQEVEE-------------------NAADVEAQIKAAFDELRNALNKRKKQ 61

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 15208641    306 ALSVVDAHVREKLIWLRQQQEDMTILLSEVSAACLHCEKTLQQDDC-RVVLAKQEITRLLETLQKQ 370
Cdd:smart00502  62 LLEDLEEQKENKLKVLEQQLESLTQKQEKLSHAINFTEEALNSGDPtELLLSKKLIIERLQNLLKQ 127

first B-box-type 2 zinc finger found in tripartite motif-containing protein 23 (TRIM23) and similar proteins; TRIM23, also known as ADP-ribosylation factor domain-containing protein 1, GTP-binding protein ARD-1, or RING finger protein 46 (RNF46), is an E3 ubiquitin-protein ligase belonging to the C-IX subclass of TRIM (tripartite motif) family of proteins that are defined by an N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a RING finger, two Bbox2, and a coiled coil region, as well as C-terminal ADP ribosylation factor (ARF) domains. The type 2 B-box (Bbox2) zinc finger is characterized by a CHC3H2 zinc-binding consensus motif. TRIM23 is involved in nuclear factor (NF)-kappaB activation. It mediates atypical lysine 27 (K27)-linked polyubiquitin conjugation to NF-kappaB essential modulator NEMO, also known as IKKgamma, which plays an important role in the NF-kappaB pathway, and this conjugation is essential for TLR3- and RIG-I/MDA5-mediated antiviral innate and inflammatory responses. It also regulates adipocyte differentiation via stabilization of the adipogenic activator peroxisome proliferator-activated receptor gamma (PPARgamma) through atypical ubiquitin conjugation to PPARgamma. Moreover, TRIM23 interacts with and polyubiquitinates yellow fever virus (YFV) NS5 to promote its binding to STAT2 and trigger type I interferon (IFN-I) signaling inhibition.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 15208641 123 SIIRCDEDEAHLASVYCTVCATHLCSECSQVTHSTKTLAKHRRVPLADKP 172
Cdd:cd19773   1 PSIPCDENEDHEATLYCTVCSTNLCEECFTSTHSTKTLSKHRRVPLSEKP 50

GTPase SAR1 family domain [General function prediction only];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15208641 404 EIRVVTLGLDGAGKTTILFKLKQDEFMQP--IPTIGFNVETVEYK----NLKFTIWDVGG---KHKLRPLWKHYYLNTQA 474
Cdd:COG1100   3 EKKIVVVGTGGVGKTSLVNRLVGDIFSLEkyLSTNGVTIDKKELKldglDVDLVIWDTPGqdeFRETRQFYARQLTGASL 82

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 15208641 475 VVFVVDSSHRD-RISEAhsELAKLLTEKELRDALLLIFaNKQDVAGALSVEEITELLSL 532
Cdd:COG1100  83 YLFVVDGTREEtLQSLY--ELLESLRRLGKKSPIILVL-NKIDLYDEEEIEDEERLKEA 138

B-Box-type zinc finger;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*..
gi 15208641    173 HEKTMCSQHQVHAIEFVCLEegCQTspLMCCVCKEYgKHQGHKHSVL 219
Cdd:smart00336   1 QRAPKCDSHGDEPAEFFCEE--CGA--LLCRTCDEA-EHRGHTVVLL 42

DNA repair protein rad18; All proteins in this family for which functions are known are involved in nucleotide excision repair.This family is based on the phylogenomic analysis of JA Eisen (1999, Ph.D. Thesis, Stanford University). [DNA metabolism, DNA replication, recombination, and repair]

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 15208641    29 LECGVCEDVFslqgdKVPRLLLCGHTVCHDCLTR-LPLHGRAIRCPFDRQVTDlgdsgvwgLKKNFALLELLERLQN 104
Cdd:TIGR00599  27 LRCHICKDFF-----DVPVLTSCSHTFCSLCIRRcLSNQPKCPLCRAEDQESK--------LRSNWLVSEIVESFKN 90

B-box zinc finger;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 15208641   125 IRCDEDEAHLASVYCTVCATHLCSECSQVTHStktlaKHRRVPL 168
Cdd:pfam00643   4 RLCPEHEEEPLTLYCNDCQELLCEECSVGEHR-----GHTVVPL 42

(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 15208641 406 RVVTLGLDGAGKTTILFKLKQDEFMQPIPTIGFNVETVEYKNLKFTIWDVGGKHKLRPLWKHYYLNTQAVVFVVDSSHRD 485
Cdd:cd04158   1 RVVTLGLDGAGKTTILFKLKQDEFMQPIPTIGFNVETVEYKNLKFTIWDVGGKHKLRPLWKHYYLNTQAVVFVIDSSHRD 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 15208641 486 RISEAHSELAKLLTEKELRDALLLIFANKQDVAGALSVEEITELLSLHKLCCGRSWYIQGCDARS 550
Cdd:cd04158  81 RVSEAHSELAKLLTEKELRDALLLIFANKQDVAGALSVEEMTELLSLHKLCCGRSWYIQGCDARS 145

ADP-ribosylation factor(Arf)/Arf-like (Arl) small GTPases; Arf (ADP-ribosylation factor)/Arl (Arf-like) small GTPases. Arf proteins are activators 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. Members of the Arf family are regulators of vesicle formation in intracellular traffic that interact reversibly with membranes of the secretory and endocytic compartments in a GTP-dependent manner. They depart from other small GTP-binding proteins by a unique structural device, interswitch toggle, that implements front-back communication from N-terminus to the nucleotide binding site. Arf-like (Arl) proteins are close relatives of the Arf, but only Arl1 has been shown to function in membrane traffic like the Arf proteins. Arl2 has an unrelated function in the folding of native tubulin, and Arl4 may function in the nucleus. Most other Arf family proteins are so far relatively poorly characterized. Thus, despite their significant sequence homologies, Arf family proteins may regulate unrelated functions.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15208641 406 RVVTLGLDGAGKTTILFKLKQDEFMQPIPTIGFNVETVEYKNLKFTIWDVGGKHKLRPLWKHYYLNTQAVVFVVDSSHRD 485
Cdd:cd00878   1 RILMLGLDGAGKTTILYKLKLGEVVTTIPTIGFNVETVEYKNVKFTVWDVGGQDKIRPLWKHYYENTDGLIFVVDSSDRE 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 15208641 486 RISEAHSELAKLLTEKELRDALLLIFANKQDVAGALSVEEITELLSLHKlCCGRSWYIQGCDARS 550
Cdd:cd00878  81 RIEEAKNELHKLLNEEELKGAPLLILANKQDLPGALTESELIELLGLES-IKGRRWHIQPCSAVT 144

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 15208641 405 IRVVTLGLDGAGKTTILFKLKQDEFMQPIPTIGFNVETVEYKNLKFTIWDVGGKHKLRPLWKHYYLNTQAVVFVVDSSHR 484
Cdd:cd04150   1 MRILMVGLDAAGKTTILYKLKLGEIVTTIPTIGFNVETVEYKNISFTVWDVGGQDKIRPLWRHYFQNTQGLIFVVDSNDR 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 15208641 485 DRISEAHSELAKLLTEKELRDALLLIFANKQDVAGALSVEEITELLSLHKLcCGRSWYIQGCDARS 550
Cdd:cd04150  81 ERIGEAREELQRMLNEDELRDAVLLVFANKQDLPNAMSAAEVTDKLGLHSL-RNRNWYIQATCATS 145

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 15208641    402 KMEIRVVTLGLDGAGKTTILFKLKQDEFMQPIPTIGFNVETVEYKNLKFTIWDVGGKHKLRPLWKHYYLNTQAVVFVVDS 481
Cdd:smart00177  11 NKEMRILMVGLDAAGKTTILYKLKLGESVTTIPTIGFNVETVTYKNISFTVWDVGGQDKIRPLWRHYYTNTQGLIFVVDS 90

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 15208641    482 SHRDRISEAHSELAKLLTEKELRDALLLIFANKQDVAGALSVEEITELLSLHKLcCGRSWYIQGCDARS 550
Cdd:smart00177  91 NDRDRIDEAREELHRMLNEDELRDAVILVFANKQDLPDAMKAAEITEKLGLHSI-RDRNWYIQPTCATS 158

ADP ribosylation factor 1 (Arf1); Arl1 subfamily. Arl1 (Arf-like 1) localizes to the Golgi complex, where it is believed to recruit effector proteins to the trans-Golgi network. Like most members of the Arf family, Arl1 is myristoylated at its N-terminal helix and mutation of the myristoylation site disrupts Golgi targeting. In humans, the Golgi-localized proteins golgin-97 and golgin-245 have been identified as Arl1 effectors. Golgins are large coiled-coil proteins found in the Golgi, and these golgins contain a C-terminal GRIP domain, which is the site of Arl1 binding. Additional Arl1 effectors include the GARP (Golgi-associated retrograde protein)/VFT (Vps53) vesicle-tethering complex and Arfaptin 2. Arl1 is not required for exocytosis, but appears necessary for trafficking from the endosomes to the Golgi. In Drosophila zygotes, mutation of Arl1 is lethal, and in the host-bloodstream form of Trypanosoma brucei, Arl1 is essential for viability.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15208641 406 RVVTLGLDGAGKTTILFKLKQDEFMQPIPTIGFNVETVEYKNLKFTIWDVGGKHKLRPLWKHYYLNTQAVVFVVDSSHRD 485
Cdd:cd04151   1 RILILGLDGAGKTTILYRLQVGEVVTTIPTIGFNVETVTYKNLKFQVWDLGGQTSIRPYWRCYYSNTDAIIYVVDSTDRD 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 15208641 486 RISEAHSELAKLLTEKELRDALLLIFANKQDVAGALSVEEITELLSLHKLcCGRSWYIQGCDA 548
Cdd:cd04151  81 RLGISKSELHAMLEEEELKDAVLLVFANKQDMPGALSEAEVAEKLGLSEL-KDRTWQIFKTSA 142

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 15208641 406 RVVTLGLDGAGKTTILFKLKQDEFMQPIPTIGFNVETVEY-KNLKFTIWDVGGKHKLRPLWKHYYLNTQAVVFVVDSSHR 484
Cdd:cd04156   1 QVLLLGLDSAGKSTLLYKLKHAELVTTIPTVGFNVEMLQLeKHLSLTVWDVGGQEKMRTVWKCYLENTDGLVYVVDSSDE 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 15208641 485 DRISEAHSELAKLLTEKELRDALLLIFANKQDVAGALSVEEITELLSLHKLCCGRSWYIQGCDA 548
Cdd:cd04156  81 ARLDESQKELKHILKNEHIKGVPVVLLANKQDLPGALTAEEITRRFKLKKYCSDRDWYVQPCSA 144

Arf-like 2 (Arl2) GTPase; Arl2 (Arf-like 2) GTPases are members of the Arf family that bind GDP and GTP with very low affinity. Unlike most Arf family proteins, Arl2 is not myristoylated at its N-terminal helix. The protein PDE-delta, first identified in photoreceptor rod cells, binds specifically to Arl2 and is structurally very similar to RhoGDI. Despite the high structural similarity between Arl2 and Rho proteins and between PDE-delta and RhoGDI, the interactions between the GTPases and their effectors are very different. In its GTP bound form, Arl2 interacts with the protein Binder of Arl2 (BART), and the complex is believed to play a role in mitochondrial adenine nucleotide transport. In its GDP bound form, Arl2 interacts with tubulin- folding Cofactor D; this interaction is believed to play a role in regulation of microtubule dynamics that impact the cytoskeleton, cell division, and cytokinesis.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15208641 404 EIRVVTLGLDGAGKTTILFKLKQDEFMQPIPTIGFNVETVEYKNLKFTIWDVGGKHKLRPLWKHYYLNTQAVVFVVDSSH 483
Cdd:cd04154  14 EMRILMLGLDNAGKTTILKKFNGEDISTISPTLGFNIKTLEYNGYKLNIWDVGGQKSLRSYWRNYFESTDALIWVVDSSD 93

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 15208641 484 RDRISEAHSELAKLLTEKELRDALLLIFANKQDVAGALSVEEITELLSLHKLcCGRSWYIQGCDA 548
Cdd:cd04154  94 RARLEDCKRELQKLLVEERLAGATLLIFANKQDLPGALSPEEIREVLELDSI-KSHHWRIFGCSA 157

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 15208641 402 KMEIRVVTLGLDGAGKTTILFKLKQDEFMQPIPTIGFNVETVEYKNLKFTIWDVGGKHKLRPLWKHYYLNTQAVVFVVDS 481
Cdd:cd00879  17 KKEAKIVFLGLDNAGKTTLLHMLKDDRLAQHVPTLHPTSEELTIGNVKFTTFDLGGHEQARRVWKDYFPEVDGIVFLVDA 96

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 15208641 482 SHRDRISEAHSELAKLLTEKELRDALLLIFANKQDVAGALSVEEITELLSLHKLCCG 538
Cdd:cd00879  97 ADPERFQESKEELDSLLNDEELANVPILILGNKIDKPGAVSEEELREALGLYGTTTG 153

Arf-like 9 (Arl9)/Arfrp2-like GTPase; Arl9/Arfrp2-like subfamily. Arl9 (Arf-like 9) was first identified as part of the Human Cancer Genome Project. It maps to chromosome 4q12 and is sometimes referred to as Arfrp2 (Arf-related protein 2). This is a novel subfamily identified in human cancers that is uncharacterized to date.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15208641 407 VVTLGLDGAGKTTILFKLKQDEFMQP-IPTIGFNVETVEYKNLKFTIWDVGGKHKLRPLWKHYYLNTQAVVFVVDSSHRD 485
Cdd:cd04162   2 ILVLGLDGAGKTSLLHSLSSERSLESvVPTTGFNSVAIPTQDAIMELLEIGGSQNLRKYWKRYLSGSQGLIFVVDSADSE 81

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 15208641 486 RISEAHSELAKLLTEKElrDALLLIFANKQDVAGALSVEEITELLSLHKLCCGRSWYIQGC 546
Cdd:cd04162  82 RLPLARQELHQLLQHPP--DLPLVVLANKQDLPAARSVQEIHKELELEPIARGRRWILQGT 140

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 15208641 404 EIRVVtlGLDGAGKTTILFKLKQDEFMQP-IPTIGFNVETVEYKNLKFTIWDVGGKHKLRPLWKHYYLNTQAVVFVVDSS 482
Cdd:cd04159   1 EITLV--GLQNSGKTTLVNVIASGQFSEDtIPTVGFNMRKVTKGNVTIKVWDLGGQPRFRSMWERYCRGVNAIVYVVDAA 78

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 15208641 483 HRDRISEAHSELAKLLTEKELRDALLLIFANKQDVAGALSVEEITELLSLHKL-----CC 537
Cdd:cd04159  79 DREKLEVAKNELHDLLEKPSLEGIPLLVLGNKNDLPGALSVDELIEQMNLKSItdrevSC 138

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 15208641    404 EIRVVTLGLDGAGKTTILFKLKQDEFMQPIPTIGFNVETVEYKNLKFTIWDVGGKHKLRPLWKHYYLNTQAVVFVVDSSH 483
Cdd:smart00178  17 HAKILFLGLDNAGKTTLLHMLKNDRLAQHQPTQHPTSEELAIGNIKFTTFDLGGHQQARRLWKDYFPEVNGIVYLVDAYD 96

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 15208641    484 RDRISEAHSELAKLLTEKELRDALLLIFANKQDVAGALSVEEITELLSLHKLCCGR 539
Cdd:smart00178  97 KERFAESKRELDALLSDEELATVPFLILGNKIDAPYAASEDELRYALGLTNTTTGK 152

Modified RING finger, HC subclass (C3HC3D-type), found in tripartite motif-containing protein 23 (TRIM23) and similar proteins; TRIM23, also known as ADP-ribosylation factor domain-containing protein 1, GTP-binding protein ARD-1, or RING finger protein 46 (RNF46), is an E3 ubiquitin-protein ligase belonging to the C-IX subclass of the TRIM (tripartite motif) family of proteins that are defined by an N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a modified C3HC3D-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as C-terminal ADP ribosylation factor (ARF) domains. TRIM23 is involved in nuclear factor (NF)-kappaB activation. It mediates atypical lysine 27 (K27)-linked polyubiquitin conjugation to NF-kappaB essential modulator NEMO, also known as IKKgamma, which plays an important role in the NF-kappaB pathway, and this conjugation is essential for TLR3- and RIG-I/MDA5-mediated antiviral innate and inflammatory responses. It also regulates adipocyte differentiation via stabilization of the adipogenic activator peroxisome proliferator-activated receptor gamma (PPARgamma) through atypical ubiquitin conjugation to PPARgamma. Moreover, TRIM23 interacts with and polyubiquitinates yellow fever virus (YFV) NS5 to promote its binding to STAT2 and trigger type I interferon (IFN-I) signaling inhibition.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 15208641  28 VLECGVCEDVFSLQGDKVPRLLLCGHTVCHDCLTRLPLHGRAIRCPFDRQ 77
Cdd:cd16645   1 VLECGVCEDVFSLQGDKVPRLLLCGHTVCHDCLTRLPLHGRAVRCPFDRQ 50

second B-box-type 2 zinc finger found in tripartite motif-containing protein 23 (TRIM23) and similar proteins; TRIM23, also known as ADP-ribosylation factor domain-containing protein 1, GTP-binding protein ARD-1, or RING finger protein 46 (RNF46), is an E3 ubiquitin-protein ligase belonging to the C-IX subclass of TRIM (tripartite motif) family of proteins that are defined by an N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a RING finger, two Bbox2, and a coiled coil region, as well as C-terminal ADP ribosylation factor (ARF) domains. The type 2 B-box (Bbox2) zinc finger is characterized by a CHC3H2 zinc-binding consensus motif. TRIM23 is involved in nuclear factor (NF)-kappaB activation. It mediates atypical lysine 27 (K27)-linked polyubiquitin conjugation to NF-kappaB essential modulator NEMO, also known as IKKgamma, which plays an important role in the NF-kappaB pathway, and this conjugation is essential for TLR3- and RIG-I/MDA5-mediated antiviral innate and inflammatory responses. It also regulates adipocyte differentiation via stabilization of the adipogenic activator peroxisome proliferator-activated receptor gamma (PPARgamma) through atypical ubiquitin conjugation to PPARgamma. Moreover, TRIM23 interacts with and polyubiquitinates yellow fever virus (YFV) NS5 to promote its binding to STAT2 and trigger type I interferon (IFN-I) signaling inhibition.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 15208641 174 EKTMCSQHQVHAIEFVCLEEGCQTSPLMCCVCKEYGKHQGHKHSVLEPEA 223
Cdd:cd19774   1 EKPKCPIHPDHLIEFVCLEEDCQESPLMCIICKEYGKHQGHKHELLEEEA 50

GTPase SAR1 family domain [General function prediction only];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15208641 404 EIRVVTLGLDGAGKTTILFKLKQDEFMQP--IPTIGFNVETVEYK----NLKFTIWDVGG---KHKLRPLWKHYYLNTQA 474
Cdd:COG1100   3 EKKIVVVGTGGVGKTSLVNRLVGDIFSLEkyLSTNGVTIDKKELKldglDVDLVIWDTPGqdeFRETRQFYARQLTGASL 82

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 15208641 475 VVFVVDSSHRD-RISEAhsELAKLLTEKELRDALLLIFaNKQDVAGALSVEEITELLSL 532
Cdd:COG1100  83 YLFVVDGTREEtLQSLY--ELLESLRRLGKKSPIILVL-NKIDLYDEEEIEDEERLKEA 138

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 15208641 404 EIRVVTLGLDGAGKTTILFKLKQDEFMQPI-PTIG--FNVETVEY--KNLKFTIWDVGGKHKLRPLWKHYYLNTQAVVFV 478
Cdd:cd01860   1 QFKLVLLGDSSVGKSSIVLRFVKNEFSENQeSTIGaaFLTQTVNLddTTVKFEIWDTAGQERYRSLAPMYYRGAAAAIVV 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 15208641 479 VDSSHRDRISEAHSELakllteKELR-----DALLLIFANKQDVAG--ALSVEEITELLSLHKL 535
Cdd:cd01860  81 YDITSEESFEKAKSWV------KELQehgppNIVIALAGNKADLESkrQVSTEEAQEYADENGL 138

Rat sarcoma (Ras)-like superfamily of small guanosine triphosphatases (GTPases); Ras-like GTPase superfamily. The Ras-like superfamily of small GTPases consists of several families with an extremely high degree of structural and functional similarity. The Ras superfamily is divided into at least four families in eukaryotes: the Ras, Rho, Rab, and Sar1/Arf families. This superfamily also includes proteins like the GTP translation factors, Era-like GTPases, and G-alpha chain of the heterotrimeric G proteins. Members of the Ras superfamily regulate a wide variety of cellular functions: the Ras family regulates gene expression, the Rho family regulates cytoskeletal reorganization and gene expression, the Rab and Sar1/Arf families regulate vesicle trafficking, and the Ran family regulates nucleocytoplasmic transport and microtubule organization. The GTP translation factor family regulates initiation, elongation, termination, and release in translation, and the Era-like GTPase family regulates cell division, sporulation, and DNA replication. Members of the Ras superfamily are identified by the GTP binding site, which is made up of five characteristic sequence motifs, and the switch I and switch II regions.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15208641 408 VTLGLDGAGKTTILFKLKQDEFMQ----PIPTIGFNVETVEY--KNLKFTIWDVGGKHKLRPLW-----KHYYLNTQAVV 476
Cdd:cd00882   1 VVVGRGGVGKSSLLNALLGGEVGEvsdvPGTTRDPDVYVKELdkGKVKLVLVDTPGLDEFGGLGreelaRLLLRGADLIL 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 15208641 477 FVVDSSHRDRISEAHSELAKLLtekELRDALLLIFANKQDVAGALSVEEITELLSLHKL 535
Cdd:cd00882  81 LVVDSTDRESEEDAKLLILRRL---RKEGIPIILVGNKIDLLEEREVEELLRLEELAKI 136

Rab family protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15208641  403 MEIRVVTLGLDGAGKTTILFKLKQDEFMQPIPTIGFNVE----TVEYKNLKFTIWDVGGKHKLRPLWKHYYLNTQAVVFV 478
Cdd:PLN03118  13 LSFKILLIGDSGVGKSSLLVSFISSSVEDLAPTIGVDFKikqlTVGGKRLKLTIWDTAGQERFRTLTSSYYRNAQGIILV 92

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|..
gi 15208641  479 VDSSHRDRISEAHSELAKlltEKEL----RDALLLIFANKQD 516
Cdd:PLN03118  93 YDVTRRETFTNLSDVWGK---EVELystnQDCVKMLVGNKVD 131

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 15208641 405 IRVVTLGLDGAGKTTILFKLKQDEF-MQPIPTIG--FNVETVEY--KNLKFTIWDVGGKHKLRPLWKHYYLNTQAVVFVV 479
Cdd:cd00154   1 FKIVLIGDSGVGKTSLLLRFVDNKFsENYKSTIGvdFKSKTIEVdgKKVKLQIWDTAGQERFRSITSSYYRGAHGAILVY 80

                ....*.
gi 15208641 480 DSSHRD 485
Cdd:cd00154  81 DVTNRE 86

Modified RING finger, HC subclass (C3HC3D-type), found in Caenorhabditis elegans putative GTP-binding protein trim-23 homolog (arc-1) and similar proteins; arc-1, also called RING-type E3 ubiquitin transferase arc-1, is an E3 ubiquitin-protein ligase that mediates E2-dependent protein ubiquitination. arc-1 contains a modified C3HC3D-type RING-HC finger.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 15208641  29 LECGVCEDVFSLQGD-KVPRLLL-CGHTVCHDCL-TRLPLHGRAIRCPFDRQVT 79
Cdd:cd23124   2 LECGICQQEYSADDPlLIPRILTeCGHTICTNCAgTILGQSSGSIFCPFDRIVT 55