ArfGAP with coiled-coil, ankyrin repeat and PH domains Pleckstrin homology (PH) domain; ACAP (also called centaurin beta) functions both as a Rab35 effector and as an Arf6-GTPase-activating protein (GAP) by which it controls actin remodeling and membrane trafficking. ACAP contain an NH2-terminal bin/amphiphysin/Rvs (BAR) domain, a phospholipid-binding domain, a PH domain, a GAP domain, and four ankyrin repeats. The AZAPs constitute a family of Arf GAPs that are characterized by an NH2-terminal pleckstrin homology (PH) domain and a central Arf GAP domain followed by two or more ankyrin repeats. On the basis of sequence and domain organization, the AZAP family is further subdivided into four subfamilies: 1) the ACAPs contain an NH2-terminal bin/amphiphysin/Rvs (BAR) domain (a phospholipid-binding domain that is thought to sense membrane curvature), a single PH domain followed by the GAP domain, and four ankyrin repeats; 2) the ASAPs also contain an NH2-terminal BAR domain, the tandem PH domain/GAP domain, three ankyrin repeats, two proline-rich regions, and a COOH-terminal Src homology 3 domain; 3) the AGAPs contain an NH2-terminal GTPase-like domain (GLD), a split PH domain, and the GAP domain followed by four ankyrin repeats; and 4) the ARAPs contain both an Arf GAP domain and a Rho GAP domain, as well as an NH2-terminal sterile-a motif (SAM), a proline-rich region, a GTPase-binding domain, and five PH domains. PMID 18003747 and 19055940 Centaurin can bind to phosphatidlyinositol (3,4,5)P3. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039751968  82 MEGYLFKRASNAFKTWNRkkpdhirRWFSIQNNQLVYQKKF-KDSPTVVVEDLRLCTVKHCEDIERRFCFEVVSPTKSCM 160
Cdd:cd13250     1 KEGYLFKRSSNAFKTWKR-------RWFSLQNGQLYYQKRDkKDEPTVMVEDLRLCTVKPTEDSDRRFCFEVISPTKSYM 73

                          90       100
                  ....*....|....*....|....*
gi 1039751968 161 LQADSEKLRQAWIKAVQTSIATAYR 185
Cdd:cd13250    74 LQAESEEDRQAWIQAIQSAIASALN 98

Ankyrin repeat [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039751968 457 LYRASYEKNLpKMAEAL-AHGADVNWANSDENqaTPLIQAVLGGSLVTCEFLLQNGANVNQRDVQGRGPLHHATVLGHTG 535
Cdd:COG0666   124 LHLAAYNGNL-EIVKLLlEAGADVNAQDNDGN--TPLHLAAANGNLEIVKLLLEAGADVNARDNDGETPLHLAAENGHLE 200

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1039751968 536 QVCLFLKRGANQHATDEEGKDPLSIAVEAANADIVTLLRLARMNEEMRESEGL 588
Cdd:COG0666   201 IVKLLLEAGADVNAKDNDGKTALDLAAENGNLEIVKLLLEAGADLNAKDKDGL 253

ArfGAP with coiled-coil, ankyrin repeat and PH domains Pleckstrin homology (PH) domain; ACAP (also called centaurin beta) functions both as a Rab35 effector and as an Arf6-GTPase-activating protein (GAP) by which it controls actin remodeling and membrane trafficking. ACAP contain an NH2-terminal bin/amphiphysin/Rvs (BAR) domain, a phospholipid-binding domain, a PH domain, a GAP domain, and four ankyrin repeats. The AZAPs constitute a family of Arf GAPs that are characterized by an NH2-terminal pleckstrin homology (PH) domain and a central Arf GAP domain followed by two or more ankyrin repeats. On the basis of sequence and domain organization, the AZAP family is further subdivided into four subfamilies: 1) the ACAPs contain an NH2-terminal bin/amphiphysin/Rvs (BAR) domain (a phospholipid-binding domain that is thought to sense membrane curvature), a single PH domain followed by the GAP domain, and four ankyrin repeats; 2) the ASAPs also contain an NH2-terminal BAR domain, the tandem PH domain/GAP domain, three ankyrin repeats, two proline-rich regions, and a COOH-terminal Src homology 3 domain; 3) the AGAPs contain an NH2-terminal GTPase-like domain (GLD), a split PH domain, and the GAP domain followed by four ankyrin repeats; and 4) the ARAPs contain both an Arf GAP domain and a Rho GAP domain, as well as an NH2-terminal sterile-a motif (SAM), a proline-rich region, a GTPase-binding domain, and five PH domains. PMID 18003747 and 19055940 Centaurin can bind to phosphatidlyinositol (3,4,5)P3. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039751968  82 MEGYLFKRASNAFKTWNRkkpdhirRWFSIQNNQLVYQKKF-KDSPTVVVEDLRLCTVKHCEDIERRFCFEVVSPTKSCM 160
Cdd:cd13250     1 KEGYLFKRSSNAFKTWKR-------RWFSLQNGQLYYQKRDkKDEPTVMVEDLRLCTVKPTEDSDRRFCFEVISPTKSYM 73

                          90       100
                  ....*....|....*....|....*
gi 1039751968 161 LQADSEKLRQAWIKAVQTSIATAYR 185
Cdd:cd13250    74 LQAESEEDRQAWIQAIQSAIASALN 98

Putative GTPase activating protein for Arf; Putative zinc fingers with GTPase activating proteins (GAPs) towards the small GTPase, Arf. The GAP of ARD1 stimulates GTPase hydrolysis for ARD1 but not ARFs.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039751968 219 ESALQRVQCIPGNTSCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRV 298
Cdd:pfam01412   1 KRVLRELLKLPGNKVCADCGAPNPTWASVNLGIFICIDCSGVHRSLGVHISKVRSLTLDTWTDEQLELMKAGGNDRANEF 80

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 1039751968 299 YEAKLEKmGVKKPQPGQRQEKEAYIRAKYVERKFVDK 335
Cdd:pfam01412  81 WEANLPP-SYKPPPSSDREKRESFIRAKYVEKKFAKP 116

Ankyrin repeat [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039751968 457 LYRASYEKNLpKMAEAL-AHGADVNWANSDENqaTPLIQAVLGGSLVTCEFLLQNGANVNQRDVQGRGPLHHATVLGHTG 535
Cdd:COG0666   124 LHLAAYNGNL-EIVKLLlEAGADVNAQDNDGN--TPLHLAAANGNLEIVKLLLEAGADVNARDNDGETPLHLAAENGHLE 200

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1039751968 536 QVCLFLKRGANQHATDEEGKDPLSIAVEAANADIVTLLRLARMNEEMRESEGL 588
Cdd:COG0666   201 IVKLLLEAGADVNAKDNDGKTALDLAAENGNLEIVKLLLEAGADLNAKDKDGL 253

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039751968   80 IVMEGYLFKRASNAFKTWNRkkpdhirRWFSIQNNQLVYQKKFKDSPTVVVE---DLRLCTVKHCEDI---ERRFCFEVV 153
Cdd:smart00233   1 VIKEGWLYKKSGGGKKSWKK-------RYFVLFNSTLLYYKSKKDKKSYKPKgsiDLSGCTVREAPDPdssKKPHCFEIK 73

                           90       100
                   ....*....|....*....|....*....
gi 1039751968  154 SPTKSCM-LQADSEKLRQAWIKAVQTSIA 181
Cdd:smart00233  74 TSDRKTLlLQAESEEEREKWVEALRKAIA 102

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039751968  80 IVMEGYLFKRASNAFKTWNRkkpdhirRWFSIQNNQLVYQKK---FKDSPTVVVEDLRLCTVKHCEDIE---RRFCFEVV 153
Cdd:pfam00169   1 VVKEGWLLKKGGGKKKSWKK-------RYFVLFDGSLLYYKDdksGKSKEPKGSISLSGCEVVEVVASDspkRKFCFELR 73

                          90       100       110
                  ....*....|....*....|....*....|..
gi 1039751968 154 SPTKSCM----LQADSEKLRQAWIKAVQTSIA 181
Cdd:pfam00169  74 TGERTGKrtylLQAESEEERKDWIKAIQSAIR 105

Ankyrin repeats (3 copies);

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039751968 492 LIQAVLGGSLVTCEFLLQNGANVNQRDVQGRGPLHHATVLGHTgQVCLFLKRGANQHATDeEGKDPLSIAVEAANADIVT 571
Cdd:pfam12796   1 LHLAAKNGNLELVKLLLENGADANLQDKNGRTALHLAAKNGHL-EIVKLLLEHADVNLKD-NGRTALHYAARSGHLEIVK 78

                  ..
gi 1039751968 572 LL 573
Cdd:pfam12796  79 LL 80

ArfGAP domain of ACAP (ArfGAP with Coiled-coil, ANK repeat and PH domains) proteins; ArfGAP domain is an essential part of ACAP proteins that play important role in endocytosis, actin remodeling and receptor tyrosine kinase-dependent cell movement. ACAP subfamily of ArfGAPs are composed of coiled coils (BAR, Bin-Amphiphysin-Rvs), PH, ArfGAP and ANK repeats domains. ACAP1 (centaurin beta1) and ACAP2 centaurin beta2) have a GAP (GTPase-activating protein) activity preferentially toward Arf6, which regulates endocytic recycling. Both ACAP1/2 are activated by are activated by the phosphoinositides, PI(4,5)P2 and PI(3,5)P2. ACAP1 binds specifically with recycling cargo proteins such as transferrin receptor (TfR) and cellubrevin. Thus, ACAP1 promotes cargo sorting to enhance TfR recycling from the recycling endosome. In addition, phosphorylation of ACAP by Akt, a serine/threonine protein kinase, regulates the recycling of integrin beta1 to control cell migration. In contrast, ACAP2 does not exhibit a similar interaction with the recycling cargo proteins. It has been shown that ACAP2 functions both as an effector of Ras-related protein Rab35 and as an Arf6-GTPase-activating protein (GAP) during neurite outgrowth of PC12 cells. In addition, ACAP2, together with Rab35, regulates phagocytosis in mammalian macrophages. ACAP3 also positively regulates neurite outgrowth through its GAP activity specific to Arf6 in mouse hippocampal neurons.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039751968 219 ESALQRVQCIPGNTSCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRV 298
Cdd:cd08835     1 GSALEQVLSVPGNAQCCDCGSPDPRWASINLGVTLCIECSGIHRSLGVHVSKVRSLTLDSWEPELLKVMLELGNDVVNRI 80

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1039751968 299 YEAKLEKMGVKKPQPG-QRQEKEAYIRAKYVERKFV 333
Cdd:cd08835    81 YEANVPDDGSVKPTPDsSRQEREAWIRAKYVEKKFV 116

ArfGAP domain of ACAP1 (ArfGAP with Coiled-coil, ANK repeat and PH domains 1); ACAP1 belongs to the ACAP subfamily of GAPs (GTPase-activating proteins) for the small GTPase Arf (ADP-ribosylation factor). ACAP subfamily of ArfGAPs are composed of Coiled coli (BAR, Bin-Amphiphysin-Rvs), PH, ArfGAP and ANK repeats domains. ACAP1 (centaurin beta1) and ACAP2 centaurin beta2) have a GAP (GTPase-activating protein) activity preferentially toward Arf6, which regulates endocytic recycling. Both ACAP1/2 are activated by are activated by the phosphoinositides, PI(4,5)P2 and PI(3,5)P2. ACAP1 binds specifically with recycling cargo proteins such as transferrin receptor (TfR) and cellubrevin. Thus, ACAP1 promotes cargo sorting to enhance TfR recycling from the recycling endosome. In addition, phosphorylation of ACAP by Akt, a serine/threonine protein kinase, regulates the recycling of integrin beta1 to control cell migration. In contrast, ACAP2 does not exhibit a similar interaction with the recycling cargo proteins. It has been shown that ACAP2 functions both as an effector of Ras-related protein Rab35 and as an Arf6-GTPase-activating protein (GAP) during neurite outgrowth of PC12 cells. Moreover, ACAP2, together with Rab35, regulates phagocytosis in mammalian macrophages. ACAP3 also positively regulates neurite outgrowth through its GAP activity specific to Arf6 in mouse hippocampal neurons.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039751968 221 ALQRVQCIPGNTSCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRVYE 300
Cdd:cd08852     3 AVAQVQSVDGNAQCCDCREPAPEWASINLGVTLCIQCSGIHRSLGVHFSKVRSLTLDSWEPELVKLMCELGNVIINQIYE 82

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1039751968 301 AKLEKMGVKKPQPG-QRQEKEAYIRAKYVERKFVDK 335
Cdd:cd08852    83 ARIEAMAIKKPGPSsSRQEKEAWIRAKYVEKKFITK 118

GTPase-activating protein (GAP) for the ADP ribosylation factors (ARFs); ArfGAPs are a family of proteins containing an ArfGAP catalytic domain that induces the hydrolysis of GTP bound to the small guanine nucleotide-binding protein Arf, a member of the Ras superfamily of GTPases. Like all GTP-binding proteins, Arf proteins function as molecular switches, cycling between GTP (active-membrane bound) and GDP (inactive-cytosolic) form. Conversion to the GTP-bound form requires a guanine nucleotide exchange factor (GEF), whereas conversion to the GDP-bound form is catalyzed by a GTPase activating protein (GAP). In that sense, ArfGAPs were originally proposed to function as terminators of Arf signaling, which is mediated by regulating Arf family GTP-binding proteins. However, recent studies suggest that ArfGAPs can also function as Arf effectors, independently of their GAP enzymatic activity to transduce signals in cells. The ArfGAP domain contains a C4-type zinc finger motif and a conserved arginine that is required for activity, within a specific spacing (CX2CX16CX2CX4R). ArfGAPs, which have multiple functional domains, regulate the membrane trafficking and actin cytoskeleton remodeling via specific interactions with signaling lipids such as phosphoinositides and trafficking proteins, which consequently affect cellular events such as cell growth, migration, and cancer invasion. The ArfGAP family, which includes 31 human ArfGAP-domain containing proteins, is divided into 10 subfamilies based on domain structure and sequence similarity. The ArfGAP nomenclature is mainly based on the protein domain structure. For example, ASAP1 contains ArfGAP, SH3, ANK repeat and PH domains; ARAPs contain ArfGAP, Rho GAP, ANK repeat and PH domains; ACAPs contain ArfGAP, BAR (coiled coil), ANK repeat and PH domains; and AGAPs contain Arf GAP, GTP-binding protein-like, ANK repeat and PH domains. Furthermore, the ArfGAPs can be classified into two major types of subfamilies, according to the overall domain structure: the ArfGAP1 type includes 6 subfamilies (ArfGAP1, ArfGAP2/3, ADAP, SMAP, AGFG, and GIT), which contain the ArfGAP domain at the N-terminus of the protein; and the AZAP type includes 4 subfamilies (ASAP, ACAP, AGAP, and ARAP), which contain an ArfGAP domain between the PH and ANK repeat domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039751968 222 LQRVQCIPGNTSCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRVYEA 301
Cdd:cd08204     1 LEELLKLPGNKVCADCGAPDPRWASINLGVFICIRCSGIHRSLGVHISKVRSLTLDSWTPEQVELMKAIGNARANAYYEA 80

                          90       100
                  ....*....|....*....|....*..
gi 1039751968 302 KLEKmGVKKPQPGQ-RQEKEAYIRAKY 327
Cdd:cd08204    81 NLPP-GFKKPTPDSsDEEREQFIRAKY 106

Putative GTPase activating protein for Arf; Putative zinc fingers with GTPase activating proteins (GAPs) towards the small GTPase, Arf. The GAP of ARD1 stimulates GTPase hydrolysis for ARD1 but not ARFs.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039751968 219 ESALQRVQCIPGNTSCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRV 298
Cdd:pfam01412   1 KRVLRELLKLPGNKVCADCGAPNPTWASVNLGIFICIDCSGVHRSLGVHISKVRSLTLDTWTDEQLELMKAGGNDRANEF 80

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 1039751968 299 YEAKLEKmGVKKPQPGQRQEKEAYIRAKYVERKFVDK 335
Cdd:pfam01412  81 WEANLPP-SYKPPPSSDREKRESFIRAKYVEKKFAKP 116

ArfGAP domain of ASAP (Arf GAP, SH3, ANK repeat and PH domains) subfamily of ADP-ribosylation factor GTPase-activating proteins; The ArfGAPs are a family of multidomain proteins with a common catalytic domain that promotes the hydrolysis of GTP bound to Arf, thereby inactivating Arf signaling. ASAP-subfamily GAPs include three members: ASAP1, ASAP2, ASAP3. The ASAP subfamily comprises Arf GAP, SH3, ANK repeat and PH domains. From the N-terminus, each member has a BAR, PH, Arf GAP, ANK repeat, and proline rich domains. Unlike ASAP3, ASAP1 and ASAP2 also have an SH3 domain at the C-terminus. ASAP1 and ASAP2 show strong GTPase-activating protein (GAP) activity toward Arf1 and Arf5 and weak activity toward Arf6. ASAP1 is a target of Src and FAK signaling that regulates focal adhesions, circular dorsal ruffles (CDR), invadopodia, and podosomes. ASAP1 GAP activity is synergistically stimulated by phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidic acid. ASAP2 is believed to function as an ArfGAP that controls ARF-mediated vesicle budding when recruited to Golgi membranes. It also functions as a substrate and downstream target for protein tyrosine kinases Pyk2 and Src, a pathway that may be involved in the regulation of vesicular transport. ASAP3 is a focal adhesion-associated ArfGAP that functions in cell migration and invasion. Similar to ASAP1, the GAP activity of ASAP3 is strongly enhanced by PIP2 via PH domain. Like ASAP1, ASAP3 associates with focal adhesions and circular dorsal ruffles. However, unlike ASAP1, ASAP3 does not localize to invadopodia or podosomes. Both ASAP 1 and 3 have been implicated in oncogenesis, as ASAP1 is highly expressed in metastatic breast cancer and ASAP3 in hepatocellular carcinoma.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039751968 220 SALQRVQCIPGNTSCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRVY 299
Cdd:cd08834     4 SIIAEVKRLPGNDVCCDCGSPDPTWLSTNLGILTCIECSGVHRELGVHVSRIQSLTLDNLGTSELLLARNLGNEGFNEIM 83

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1039751968 300 EAKLEkmGVKKPQPG-QRQEKEAYIRAKYVERKFV 333
Cdd:cd08834    84 EANLP--PGYKPTPNsDMEERKDFIRAKYVEKKFV 116

ArfGap with dual PH domains; The ADAP subfamily, ArfGAPs with dual pleckstrin homology (PH) domains, includes two members: ADAP1 and ADAP2. Both ADAP1 (also known as centaurin-alpha1, p42(IP4), or PIP3BP) and ADAP2 (centaurin-alpha2) display a GTPase-activating protein (GAP) activity toward Arf6 (ADP-ribosylation factor 6), which is involved in protein trafficking that regulates endocytic recycling, cytoskeleton remodeling, and neuronal differentiation. ADAP2 has high sequence similarity to the ADAP1 and they both contain a ArfGAP domain at the N-terminus, followed by two PH domains. However, ADAP1, unlike ADAP2, contains a putative N-terminal nuclear localization signal. The PH domains of ADAP1bind to the two second messenger molecules phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) and inositol 1,3,4,5-tetrakisphosphate (I(1,3,4,5)P4) with identical high affinity, whereas those of ADAP2 specifically binds phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) and PI(3,4,5)P3, which are produced by activated phosphatidylinositol 3-kinase. ADAP1 is predominantly expressed in the brain neurons, while ADAP2 is broadly expressed, including the adipocytes, heart, and skeletal muscle but not in the brain. The limited distribution and high expression of ADAP1 in the brain indicates that ADAP1 is important for neuronal functions. ADAP1 has been shown to highly expressed in the neurons and plagues of Alzheimer's disease patients. In other hand, ADAP2 gene deletion has been shown to cause circulatory deficiencies and heart shape defects in zebrafish, indicating that ADAP2 has a vital role in heart development. Taken together, the hemizygous deletion of ADAP2 gene may be contributing to the cardiovascular malformation in patients with neurofibromatosis type 1 (NF1) microdeletions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039751968 221 ALQRVQCIPGNTSCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRVYE 300
Cdd:cd08832     7 RLLELLKLPGNNTCADCGAPDPEWASYNLGVFICLDCSGIHRSLGTHISKVKSLRLDNWDDSQVEFMEENGNEKAKAKYE 86

                          90       100
                  ....*....|....*....|....*...
gi 1039751968 301 AKLEKmGVKKPQPGQRQE-KEAYIRAKY 327
Cdd:cd08832    87 AHVPA-FYRRPTPTDPQVlREQWIRAKY 113

ArfGAP with GTPase domain, ANK repeat and PH domain 2; The AGAP subfamily of ADP-ribosylation factor GTPase-activating proteins (Arf GAPs) includes three members: AGAP1-3. In addition to the Arf GAP domain, AGAP proteins contain GTP-binding protein-like, ANK repeat and pleckstrin homology (PH) domains. AGAP1 and AGAP2 have phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-mediated GTPase-activating protein (GAP) activity preferentially toward Arf1, and function in the endocytic system. AGAP1 and AGAP2 independently regulate AP-3 endosomes and AP-1/Rab4 fast recycling endosomes, respectively. AGAP1, via its PH domain, directly interacts with the adapter protein 3 (AP-3), which is a coat protein involved in trafficking in the endosomal-lysosomal system, and regulates AP-3-dependent trafficking. In other hand, AGAP2 specifically binds the clathrin adaptor protein AP-1 and regulates the AP-1/Rab-4 dependent endosomal trafficking. AGAP2 is overexpressed in different human cancers including prostate carcinoma and glioblastoma, and promotes cancer cell invasion. AGAP3 exists as a component of the NMDA receptor complex that regulates Arf6 and Ras/ERK signaling pathways. Moreover, AGAP3 regulates AMPA receptor trafficking through the ArfGAP domain. Together, AGAP3 is believed to involve in linking NMDA receptor activation to AMPA receptor trafficking.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039751968 221 ALQRVQCIPGNTSCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRVYE 300
Cdd:cd08853     3 ALQSIRNMRGNSHCVDCETQNPKWASLNLGVLMCIECSGIHRNLGTHLSRVRSLDLDDWPVELRKVMSSIGNELANSIWE 82

                          90       100
                  ....*....|....*....|....*...
gi 1039751968 301 AklEKMGVKKPQ-PGQRQEKEAYIRAKY 327
Cdd:cd08853    83 G--SSQGQTKPSsDSTREEKERWIRAKY 108

ArfGAP domain of ASAP3 (ArfGAP with ANK repeat and PH domain-containing protein 3); The ArfGAPs are a family of multidomain proteins with a common catalytic domain that promotes the hydrolysis of GTP bound to Arf, thereby inactivating Arf signaling. ASAP-subfamily GAPs include three members: ASAP1, ASAP2, ASAP3. The ASAP subfamily comprises Arf GAP, SH3, ANK repeat and PH domains. From the N-terminus, each member has a BAR, PH, Arf GAP, ANK repeat, and proline rich domains. Unlike ASAP1 and ASAP2, ASAP3 do not have an SH3 domain at the C-terminus. ASAP1 and ASAP2 show strong GTPase-activating protein (GAP) activity toward Arf1 and Arf5 and weak activity toward Arf6. ASAP1 is a target of Src and FAK signaling that regulates focal adhesions, circular dorsal ruffles (CDR), invadopodia, and podosomes. ASAP1 GAP activity is synergistically stimulated by phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidic acid. ASAP2 is believed to function as an ArfGAP that controls ARF-mediated vesicle budding when recruited to Golgi membranes. It also functions as a substrate and downstream target for protein tyrosine kinases Pyk2 and Src, a pathway that may be involved in the regulation of vesicular transport. ASAP3 is a focal adhesion-associated ArfGAP that functions in cell migration and invasion. Similar to ASAP1, the GAP activity of ASAP3 is strongly enhanced by PIP2 via PH domain. Like ASAP1, ASAP3 associates with focal adhesions and circular dorsal ruffles. However, unlike ASAP1, ASAP3 does not localize to invadopodia or podosomes. ASAP 1 and 3 have been implicated in oncogenesis, as ASAP1 is highly expressed in metastatic breast cancer and ASAP3 in hepatocellular carcinoma.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039751968 225 VQCIPGNTSCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRVYEAKLE 304
Cdd:cd17900     9 VKSRPGNSQCCDCGAPDPTWLSTNLGILTCIECSGIHRELGVRYSRIQSLTLDLLSTSELLLAVSMGNTRFNEVMEATLP 88

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1039751968 305 KMGVKKPQP----GQRQEkeaYIRAKYVERKFVDK 335
Cdd:cd17900    89 AHGGPKPSAesdmGTRKD---YIMAKYVEHRFVRK 120

ArfGAP domain of ASAP2 (ArfGAP2 with SH3 domain, ANK repeat and PH domain-containing protein 2); The Arf GAPs are a family of multidomain proteins with a common catalytic domain that promotes the hydrolysis of GTP bound to Arf , thereby inactivating Arf signaling. ASAP-subfamily GAPs include three members: ASAP1, ASAP2, ASAP3. The ASAP subfamily comprises Arf GAP, SH3, ANK repeat and PH domains. From the N-terminus, each member has a BAR, PH, Arf GAP, ANK repeat, and proline rich domains. Unlike ASAP3, ASAP1 and ASAP2 also have an SH3 domain at the C-terminus. ASAP1 and ASAP2 show strong GTPase-activating protein (GAP) activity toward Arf1 and Arf5 and weak activity toward Arf6. ASAP1 is a target of Src and FAK signaling that regulates focal adhesions, circular dorsal ruffles (CDR), invadopodia, and podosomes. ASAP1 GAP activity is synergistically stimulated by phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidic acid. ASAP2 is believed to function as an ArfGAP that controls ARF-mediated vesicle budding when recruited to Golgi membranes. It also functions as a substrate and downstream target for protein tyrosine kinases Pyk2 and Src, a pathway that may be involved in the regulation of vesicular transport.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039751968 222 LQRVQCIPGNTSCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRVYEA 301
Cdd:cd08849     6 ISEVQRMTGNDVCCDCGAPDPTWLSTNLGILTCIECSGIHRELGVHYSRMQSLTLDVLGTSELLLAKNIGNAGFNEIMEA 85

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1039751968 302 KLEKMGVKKPQPGQ-RQEKEAYIRAKYVERKFVDK 335
Cdd:cd08849    86 CLPAEDVVKPNPGSdMNARKDYITAKYIERRYARK 120

ArfGAP domain of ASAP1 (ArfGAP with SH3 domain, ANK repeat and PH domain-containing protein 1); The ArfGAPs are a family of multidomain proteins with a common catalytic domain that promotes the hydrolysis of GTP bound to Arf, thereby inactivating Arf signaling. ASAP-subfamily GAPs include three members: ASAP1, ASAP2, ASAP3. The ASAP subfamily comprises Arf GAP, SH3, ANK repeat and PH domains. From the N-terminus, each member has a BAR, PH, Arf GAP, ANK repeat, and proline rich domains. Unlike ASAP3, ASAP1 and ASAP2 also have an SH3 domain at the C-terminus. ASAP1 and ASAP2 show strong GTPase-activating protein (GAP) activity toward Arf1 and Arf5 and weak activity toward Arf6. ASAP1 is a target of Src and FAK signaling that regulates focal adhesions, circular dorsal ruffles (CDR), invadopodia, and podosomes. ASAP1 GAP activity is synergistically stimulated by phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidic acid. ASAP2 is believed to function as an ArfGAP that controls ARF-mediated vesicle budding when recruited to Golgi membranes. It also functions as a substrate and downstream target for protein tyrosine kinases Pyk2 and Src, a pathway that may be involved in the regulation of vesicular transport. ASAP3 is a focal adhesion-associated ArfGAP that functions in cell migration and invasion. Similar to ASAP1, the GAP activity of ASAP3 is strongly enhanced by PIP2 via PH domain. Like ASAP1, ASAP3 associates with focal adhesions and circular dorsal ruffles. However, unlike ASAP1, ASAP3 does not localize to invadopodia or podosomes. ASAP 1 and 3 have been implicated in oncogenesis, as ASAP1 is highly expressed in metastatic breast cancer and ASAP3 in hepatocellular carcinoma.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039751968 219 ESALQRVQCIPGNTSCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRV 298
Cdd:cd08848     3 KAIIDDVQRLPGNEVCCDCGSPDPTWLSTNLGILTCIECSGIHREMGVHISRIQSLELDKLGTSELLLAKNVGNNSFNDI 82

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 1039751968 299 YEAKLEKMGVKKPQPGQRQEKEAYIRAKYVERKFVDK 335
Cdd:cd08848    83 MEGNLPSPSPKPSPSSDMTARKEYITAKYVEHRFSRK 119

ArfGap with Rho-Gap domain, ANK repeat and PH domain-containing proteins; The ARAP subfamily includes three members, ARAP1-3, and belongs to the ADP-ribosylation factor GTPase-activating proteins (Arf GAPs) family of proteins that promotes the hydrolysis of GTP bound to Arf, thereby inactivating Arf signaling. The function of Arfs is dependent on GAPs and guanine nucleotide exchange factors (GEFs), which allow Arfs to cycle between the GDP-bound and GTP-bound forms. In addition to the Arf GAP domain, ARAPs contain the SAM (sterile-alpha motif) domain, 5 pleckstrin homology (PH) domains, the Rho-GAP domain, the Ras-association domain, and ANK repeats. ARAPs show phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3)-dependent GAP activity toward Arf6. ARAPs play important roles in endocytic trafficking, cytoskeleton reorganization in response to growth factors stimulation, and focal adhesion dynamics.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039751968 222 LQRVQCIPGNTSCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDT--WEPELLKLMCELGNDVINRVY 299
Cdd:cd08837     4 AEKIWSNPANRFCADCGAPDPDWASINLCVVICKQCAGEHRSLGSNISKVRSLKMDTkvWTEELVELFLKLGNDRANRFW 83

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1039751968 300 EAKLEKMGVKKPQ--PGQRQEkeaYIRAKYVERKF 332
Cdd:cd08837    84 AANLPPSEALHPDadSEQRRE---FITAKYREGKY 115

ARF1 GTPase-activating protein 1-like; ArfGAP (ADP Ribosylation Factor GTPase Activating Protein) domain is a part of ArfGap1-like proteins that play a crucial role in controlling of membrane trafficking, particularly in the formation of COPI (coat protein complex I)-coated vesicles on Golgi membranes. The ArfGAP1 protein subfamily consists of three members: ArfGAP1 (Gcs1p in yeast), ArfGAP2 and ArfGAP3 (both are homologs of yeast Glo3p). ArfGAP2/3 are closely related, but with little similarity to ArfGAP1, except the catalytic ArfGAP domain. They promote hydrolysis of GTP bound to the small G protein ADP-ribosylation factor 1 (Arf1), which leads to the dissociation of coat proteins from Golgi-derived membranes and vesicles. Dissociation of the coat proteins is required for the fusion of these vesicles with target compartments. Thus, the GAP catalytic activity plays a key role in the formation of COPI vesicles from Golgi membrane. In contrast to ArfGAP1, which displays membrane curvature-dependent ArfGAP activity, ArfGAP2 and ArfGAP3 activities are dependent on coatomer (the core COPI complex) which required for efficient recruitment of ArfGAP2 and ArfGAP3 to the Golgi membrane. Accordingly, ArfGAP2/3 has been implicated in coatomer-mediated protein transport between the Golgi complex and the endoplasmic reticulum. Unlike ArfGAP1, which is controlled by membrane curvature through its amphipathic lipid packing sensor (ALPS) motifs, ArfGAP2/3 do not possess ALPS motif.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1039751968 222 LQRVQCIPGNTSCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLM 287
Cdd:cd08959     5 FKKLRSKPENKVCFDCGAKNPQWASVTYGIFICLDCSGVHRGLGVHISFVRSTTMDKWTEEQLRKM 70

Ankyrin repeat [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039751968 457 LYRASYEKNLpKMAEAL-AHGADVNWANSDENqaTPLIQAVLGGSLVTCEFLLQNGANVNQRDVQGRGPLHHATVLGHTG 535
Cdd:COG0666   124 LHLAAYNGNL-EIVKLLlEAGADVNAQDNDGN--TPLHLAAANGNLEIVKLLLEAGADVNARDNDGETPLHLAAENGHLE 200

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1039751968 536 QVCLFLKRGANQHATDEEGKDPLSIAVEAANADIVTLLRLARMNEEMRESEGL 588
Cdd:COG0666   201 IVKLLLEAGADVNAKDNDGKTALDLAAENGNLEIVKLLLEAGADLNAKDKDGL 253

ADAP1 GTPase activating protein for Arf, with dual PH domains; The ADAP subfamily, ArfGAPs with dual pleckstrin homology (PH) domains, includes two members: ADAP1 and ADAP2. Both ADAP1 (also known as centaurin-alpha1, p42(IP4), or PIP3BP) and ADAP2 (centaurin-alpha2) display a GTPase-activating protein (GAP) activity toward Arf6 (ADP-ribosylation factor 6), which is involved in protein trafficking that regulates endocytic recycling, cytoskeleton remodeling, and neuronal differentiation. ADAP2 has high sequence similarity to the ADAP1 and they both contain a ArfGAP domain at the N-terminus, followed by two PH domains. However, ADAP1, unlike ADAP2, contains a putative N-terminal nuclear localization signal. The PH domains of ADAP1bind to the two second messenger molecules phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) and inositol 1,3,4,5-tetrakisphosphate (I(1,3,4,5)P4) with identical high affinity, whereas those of ADAP2 specifically binds phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) and PI(3,4,5)P3, which are produced by activated phosphatidylinositol 3-kinase. ADAP1 is predominantly expressed in the brain neurons, while ADAP2 is broadly expressed, including the adipocytes, heart, and skeletal muscle but not in the brain. The limited distribution and high expression of ADAP1 in the brain indicates that ADAP1 is important for neuronal functions. ADAP1 has been shown to highly expressed in the neurons and plagues of Alzheimer's disease patients. In other hand, ADAP2 gene deletion has been shown to cause circulatory deficiencies and heart shape defects in zebrafish, indicating that ADAP2 has a vital role in heart development. Taken together, the hemizygous deletion of ADAP2 gene may be contributing to the cardiovascular malformation in patients with neurofibromatosis type 1 (NF1) microdeletions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039751968 222 LQRvqciPGNTSCCDCGLADPRWASINLGITLCIECSGIHRSLGvHFSKVRSLTLDTWEPELLKLMCELGNDVINRVYEA 301
Cdd:cd08843    12 LQR----PGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNIP-QVSKVKSVRLDAWEEAQVEFMASHGNDAARARFES 86

                          90       100
                  ....*....|....*....|....*..
gi 1039751968 302 KLEKMgVKKPQPGQRQ-EKEAYIRAKY 327
Cdd:cd08843    87 KVPSF-YYRPTPSDCQlLREQWIRAKY 112

ADAP2 GTPase activating protein for Arf, with dual PH domains; The ADAP subfamily, ArfGAPs with dual pleckstrin homology (PH) domains, includes two members: ADAP1 and ADAP2. Both ADAP1 (also known as centaurin-alpha1, p42(IP4), or PIP3BP) and ADAP2 (centaurin-alpha2) display a GTPase-activating protein (GAP) activity toward Arf6 (ADP-ribosylation factor 6), which is involved in protein trafficking that regulates endocytic recycling, cytoskeleton remodeling, and neuronal differentiation. ADAP2 has high sequence similarity to the ADAP1 and they both contain a ArfGAP domain at the N-terminus, followed by two PH domains. However, ADAP1, unlike ADAP2, contains a putative N-terminal nuclear localization signal. The PH domains of ADAP1bind to the two second messenger molecules phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) and inositol 1,3,4,5-tetrakisphosphate (I(1,3,4,5)P4) with identical high affinity, whereas those of ADAP2 specifically binds phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) and PI(3,4,5)P3, which are produced by activated phosphatidylinositol 3-kinase. ADAP1 is predominantly expressed in the brain neurons, while ADAP2 is broadly expressed, including the adipocytes, heart, and skeletal muscle but not in the brain. The limited distribution and high expression of ADAP1 in the brain indicates that ADAP1 is important for neuronal functions. ADAP1 has been shown to highly expressed in the neurons and plagues of Alzheimer's disease patients. In other hand, ADAP2 gene deletion has been shown to cause circulatory deficiencies and heart shape defects in zebrafish, indicating that ADAP2 has a vital role in heart development. Taken together, the hemizygous deletion of ADAP2 gene may be contributing to the cardiovascular malformation in patients with neurofibromatosis type 1 (NF1) microdeletions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039751968 229 PGNTSCCDCGLADPRWASINLGITLCIECSGIHRSLGvHFSKVRSLTLDTWEPELLKLMCELGNDVINRVYEAKLEKMGV 308
Cdd:cd08844    15 PGNSVCADCGAPDPDWASYTLGIFICLNCSGVHRNLP-DISRVKSIRLDFWEDELVEFMKENGNLKAKAKFEAFVPPFYY 93

                          90
                  ....*....|....*....
gi 1039751968 309 KKPQPGQRQEKEAYIRAKY 327
Cdd:cd08844    94 RPQANDCDVLKEQWIRAKY 112

ArfGap with Rho-Gap domain, ANK repeat and PH domain-containing protein 2; The ARAP subfamily includes three members, ARAP1-3, and belongs to the ADP-ribosylation factor GTPase-activating proteins (Arf GAPs) family of proteins that promotes the hydrolysis of GTP bound to Arf, thereby inactivating Arf signaling. The function of Arfs is dependent on GAPs and guanine nucleotide exchange factors (GEFs), which allow Arfs to cycle between the GDP-bound and GTP-bound forms. In addition to the Arf GAP domain, ARAPs contain the SAM (sterile-alpha motif) domain, 5 pleckstrin homology (PH) domains, the Rho-GAP domain, the Ras-association domain, and ANK repeats. ARAPs show phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3)-dependent GAP activity toward Arf6. ARAPs play important roles in endocytic trafficking, cytoskeleton reorganization in response to growth factors stimulation, and focal adhesion dynamics. ARAP2 localizes to the cell periphery and on focal adhesions composed of paxillin and vinculin, and functions downstream of RhoA to regulate focal adhesion dynamics. ARAP2 is a PI(3,4,5)P3-dependent Arf6 GAP that binds RhoA-GTP, but it lacks the predicted catalytic arginine in the RhoGAP domain and does not have RhoGAP activity. ARAP2 reduces Rac1oGTP levels by reducing Arf6oGTP levels through GAP activity. AGAP2 also binds to and regulates focal adhesion kinase (FAK). Thus, ARAP2 signals through Arf6 and Rac1 to control focal adhesion morphology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039751968 231 NTSCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDT--WEPELLKLMCELGNDVINRVYEAKLEKmGV 308
Cdd:cd08856    18 NRSCADCKAPDPDWASINLCVVICKKCAGQHRSLGPKDSKVRSLKMDAsiWSNELIELFIVVGNKPANLFWAANLFS-EE 96

                          90       100
                  ....*....|....*....|....
gi 1039751968 309 KKPQPGQRQEKEAYIRAKYVERKF 332
Cdd:cd08856    97 DLHMDSDVEQRTPFITQKYKEGKF 120

Arf1 GTPase-activating protein 2; ArfGAP (ADP Ribosylation Factor GTPase Activating Protein) domain is a part of ArfGap1-like proteins that play a crucial role in controlling of membrane trafficking, particularly in the formation of COPI (coat protein complex I)-coated vesicles on Golgi membranes. The ArfGAP1 protein subfamily consists of three members: ArfGAP1 (Gcs1p in yeast), ArfGAP2 and ArfGAP3 (both are homologs of yeast Glo3p). ArfGAP2/3 are closely related, but with little similarity to ArfGAP1, except the catalytic ArfGAP domain. They promote hydrolysis of GTP bound to the small G protein ADP-ribosylation factor 1 (Arf1), which leads to the dissociation of coat proteins from Golgi-derived membranes and vesicles. Dissociation of the coat proteins is required for the fusion of these vesicles with target compartments. Thus, the GAP catalytic activity plays a key role in the formation of COPI vesicles from Golgi membrane. In contrast to ArfGAP1, which displays membrane curvature-dependent ArfGAP activity, ArfGAP2 and ArfGAP3 activities are dependent on coatomer (the core COPI complex) which required for efficient recruitment of ArfGAP2 and ArfGAP3 to the Golgi membrane. Accordingly, ArfGAP2/3 has been implicated in coatomer-mediated protein transport between the Golgi complex and the endoplasmic reticulum. Unlike ArfGAP1, which is controlled by membrane curvature through its amphipathic lipid packing sensor (ALPS) motifs, ArfGAP2/3 do not possess ALPS motif.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1039751968 219 ESALQRVQCIPGNTSCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDT-WEPELLKLMCELGN 292
Cdd:cd09029     7 QTLFKRLRAIPTNKACFDCGAKNPSWASITYGVFLCIDCSGVHRSLGVHLSFIRSTELDSnWNWFQLRCMQVGGN 81

ArfGAP domain of the AGFG subfamily (ArfGAP domain and FG repeat-containing proteins); The ArfGAP domain and FG repeat-containing proteins (AFGF) subfamily of Arf GTPase-activating proteins consists of the two structurally-related members: AGFG1 and AGFG2. AGFG1 (alias: HIV-1 Rev binding protein, HRB; Rev interacting protein, RIP; Rev/Rex activating domain-binding protein, RAB) and AGFG2 are involved in the maintenance and spread of immunodeficiency virus type 1 (HIV-1) infection. The ArfGAP domain of AGFG is related to nucleoporins, which is a class of proteins that mediate nucleocytoplasmic transport. AGFG plays a role in the Rev export pathway, which mediates the nucleocytoplasmic transfer of proteins and RNAs, possibly together by the nuclear export receptor CRM1. In humans, the presence of the FG repeat motifs (11 in AGFG1 and 7 in AGFG2) are thought to be required for these proteins to act as HIV-1 Rev cofactors. Hence, AGFG promotes movement of Rev-responsive element-containing RNAs from the nuclear periphery to the cytoplasm, which is an essential step for HIV-1 replication.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039751968 229 PGNTSCCDCGLADPRWASINLGITLCIECSGIHRSLGvHfsKVRSLTLDTWEPELLKLMCELGNDVINRVYEAKLEKMGV 308
Cdd:cd08838    11 PENKRCFDCGQRGPTYVNLTFGTFVCTTCSGIHREFN-H--RVKSISMSTFTPEEVEFLQAGGNEVARKIWLAKWDPRTD 87

                          90       100
                  ....*....|....*....|....*.
gi 1039751968 309 KKPQPGQRQEKEAYIRAKYVERKFVD 334
Cdd:cd08838    88 PEPDSGDDQKIREFIRLKYVDKRWYD 113