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 2462554758   1 MSRKGPRAEVCADCSAPDPGWASISRGVLVCDECCSVHRSLGRHISIVKHLRHSAWPPTLLQMVHTLASNGANSIWEHSL 80
Cdd:cd08846     1 MSRKGPRAEVCADCSAPDPGWASINRGVLICDECCSVHRSLGRHISIVKHLRHSAWPPTLLQMVHTLASNGANSIWEHSL 80

                          90       100       110
                  ....*....|....*....|....*....|.
gi 2462554758  81 LDPAQVQSGRRKANPQDKVHPIKSEFIRAKY 111
Cdd:cd08846    81 LDPAQVQSGRRKANPQDKVHPTKSEFIRAKY 111

GIT coiled-coil Rho guanine nucleotide exchange factor; GIT-CC is the coiled-coil region of GIT (G protein-coupled receptor kinase-interacting) proteins. This coiled-coil region is the surface that associates with the equivalent binding-region on beta-PIX, or p21-activated kinase-interacting exchange factor proteins. Both GIT and PIX complex together to form a scaffold for the formation of multi-protein assemblies. On its own the GIT-CC region assembles into a parallel two-stranded CC in the asymmetric unit. Similarly the PIX coiled-coil region assembles into a trimer. At least in vitro the two regions associate together into a stable heteropentameric complex that consists of one PIX trimer and one GIT dimer.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 2462554758 418 RSMDSSDLSDGAVTLQEYLELKKALATSEAKVQQLMKVNSSLSDELRRLQREIHKLQAENLQLRQ 482
Cdd:pfam16559   1 KSLDSSDLSDGPVTVQEYLELKEALAASEAKIQQLMKVNTNLSDELRLLQSKVQTLQQENADLRD 65

Spa2 homology domain (SHD) of GIT; GIT proteins are signaling integrators with GTPase-activating function which may be involved in the organization of the cytoskeletal matrix assembled at active zones (CAZ). The function of the CAZ might be to define sites of neurotransmitter release. Mutations in the Spa2 homology domain (SHD) domain of GIT1 described here interfere with the association of GIT1 with Piccolo, beta-PIX, and focal adhesion kinase.

                          10        20
                  ....*....|....*....|....*....
gi 2462554758 337 GRQKLARFNAREFATLIIDILSEAKRRQQ 365
Cdd:pfam08518   1 ARQKLARLSNQQFEELVTDVYDELDRRQT 29

GIT1 GTPase activating protein for Arf; The GIT (G-protein coupled receptor kinase-interacting protein) subfamily includes GIT1 and GIT2, which have three ANK repeats, a Spa-homology domain (SHD), a coiled-coil domain and a C-terminal paxillin-binding site (PBS). The GIT1/2 proteins are GTPase-activating proteins that function as an inactivator of Arf signaling, and interact with the PIX/Cool family of Rac/Cdc42 guanine nucleotide exchange factors (GEFs). Unlike other ArfGAPs, GIT and PIX (Pak-interacting exchange factor) proteins are tightly associated to form an oligomeric complex that acts as a scaffold and signal integrator that can be recruited for multiple signaling pathways. The GIT/PIX complex functions as a signaling scaffold by binding to specific protein partners. As a result, the complex is transported to specific cellular locations. For instance, the GIT partners paxillin or integrin-alpha4 (to focal adhesions), piccolo and liprin-alpha (to synapses), and the beta-PIX partner Scribble (to epithelial cell-cell contacts and synapses). Moreover, the GIT/PIT complex functions to integrate signals from multiple GTP-binding protein and protein kinase pathways to regulate the actin cytoskeleton and thus cell polarity, adhesion and migration.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462554758   1 MSRKGPRAEVCADCSAPDPGWASISRGVLVCDECCSVHRSLGRHISIVKHLRHSAWPPTLLQMVHTLASNGANSIWEHSL 80
Cdd:cd08846     1 MSRKGPRAEVCADCSAPDPGWASINRGVLICDECCSVHRSLGRHISIVKHLRHSAWPPTLLQMVHTLASNGANSIWEHSL 80

                          90       100       110
                  ....*....|....*....|....*....|.
gi 2462554758  81 LDPAQVQSGRRKANPQDKVHPIKSEFIRAKY 111
Cdd:cd08846    81 LDPAQVQSGRRKANPQDKVHPTKSEFIRAKY 111

G protein-coupled receptor kinase-interacting protein 1 C term; This domain family is found in eukaryotes, and is approximately 120 amino acids in length. The family is found in association with pfam01412, pfam00023, pfam08518. GIT1 plays an important role in cell adhesion, motility, cytoskeletal remodelling and membrane trafficking. To perform this function, it localizes p21-activated kinase (PAK) and PAK-interactive exchange factor to focal adhesions. Its activation is regulated by interaction between its paxillin-binding C terminal and the LD motifs of paxillin. The C terminal folds into a four helix bundle.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462554758 652 EDVILKTEQVTKNIQELLRAAQEFKHDSFVPCSEKIHLAVTEMASLFPKphscplqRPALEPVRSSLRLLNASAYRLQSE 731
Cdd:pfam12205   2 DNVVRQTELITKAIQELLKAAQEGRHSEFLDCAERIRSAVTEMAALFPK-------SPRSETVREALKALTDAADKLQAE 74

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 2462554758 732 CrKTVPPEPGAPvdfqLLTQQVIQCAYDIAKAAKQLVTITT 772
Cdd:pfam12205  75 C-VSLKASPGPD----DSSQEIITAAYDIAKAAKELVTLFE 110

GIT coiled-coil Rho guanine nucleotide exchange factor; GIT-CC is the coiled-coil region of GIT (G protein-coupled receptor kinase-interacting) proteins. This coiled-coil region is the surface that associates with the equivalent binding-region on beta-PIX, or p21-activated kinase-interacting exchange factor proteins. Both GIT and PIX complex together to form a scaffold for the formation of multi-protein assemblies. On its own the GIT-CC region assembles into a parallel two-stranded CC in the asymmetric unit. Similarly the PIX coiled-coil region assembles into a trimer. At least in vitro the two regions associate together into a stable heteropentameric complex that consists of one PIX trimer and one GIT dimer.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 2462554758 418 RSMDSSDLSDGAVTLQEYLELKKALATSEAKVQQLMKVNSSLSDELRRLQREIHKLQAENLQLRQ 482
Cdd:pfam16559   1 KSLDSSDLSDGPVTVQEYLELKEALAASEAKIQQLMKVNTNLSDELRLLQSKVQTLQQENADLRD 65

Ankyrin repeat [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462554758 123 RDDDGVTAkdlskqLHSSVRTGNLETCLRLLSLGAQANFFHPEkGTTPLHVAAKAGQTLQAELLVVYGADPGSPDVNGRT 202
Cdd:COG0666   149 QDNDGNTP------LHLAAANGNLEIVKLLLEAGADVNARDND-GETPLHLAAENGHLEIVKLLLEAGADVNAKDNDGKT 221

                          90
                  ....*....|....*....
gi 2462554758 203 PIDYARQAGHHELAERLVE 221
Cdd:COG0666   222 ALDLAAENGNLEIVKLLLE 240

ADP-ribosylation factor GTPase-activating protein AGD10; Provisional

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 2462554758   9 EVCADCSAPDPGWASISRGVLVCDECCSVHRSLGRHISIVKHLRHSAWPPTLLQMV 64
Cdd:PLN03114   23 KICFDCNAKNPTWASVTYGIFLCIDCSAVHRSLGVHISFVRSTNLDSWSSEQLKMM 78

Helical motif in the GIT family of ADP-ribosylation factor GTPase-activating proteins; Helical motif in the GIT family of ADP-ribosylation factor GTPase-activating proteins, and in yeast Spa2p and Sph1p (CPP; unpublished results). In p95-APP1 the N-terminal GIT motif might be involved in binding PIX.

                           10        20        30
                   ....*....|....*....|....*....|.
gi 2462554758  337 GRQKLARFNAREFATLIIDILSEAKRRQQGK 367
Cdd:smart00555   1 ARQKLARLSDEQFQKLLTDLNDELKRRENEA 31

Spa2 homology domain (SHD) of GIT; GIT proteins are signaling integrators with GTPase-activating function which may be involved in the organization of the cytoskeletal matrix assembled at active zones (CAZ). The function of the CAZ might be to define sites of neurotransmitter release. Mutations in the Spa2 homology domain (SHD) domain of GIT1 described here interfere with the association of GIT1 with Piccolo, beta-PIX, and focal adhesion kinase.

                          10        20
                  ....*....|....*....|.
gi 2462554758 281 SNRLFEELAMDVYDEVDRREN 301
Cdd:pfam08518   9 SNQQFEELVTDVYDELDRRQT 29

GIT1 GTPase activating protein for Arf; The GIT (G-protein coupled receptor kinase-interacting protein) subfamily includes GIT1 and GIT2, which have three ANK repeats, a Spa-homology domain (SHD), a coiled-coil domain and a C-terminal paxillin-binding site (PBS). The GIT1/2 proteins are GTPase-activating proteins that function as an inactivator of Arf signaling, and interact with the PIX/Cool family of Rac/Cdc42 guanine nucleotide exchange factors (GEFs). Unlike other ArfGAPs, GIT and PIX (Pak-interacting exchange factor) proteins are tightly associated to form an oligomeric complex that acts as a scaffold and signal integrator that can be recruited for multiple signaling pathways. The GIT/PIX complex functions as a signaling scaffold by binding to specific protein partners. As a result, the complex is transported to specific cellular locations. For instance, the GIT partners paxillin or integrin-alpha4 (to focal adhesions), piccolo and liprin-alpha (to synapses), and the beta-PIX partner Scribble (to epithelial cell-cell contacts and synapses). Moreover, the GIT/PIT complex functions to integrate signals from multiple GTP-binding protein and protein kinase pathways to regulate the actin cytoskeleton and thus cell polarity, adhesion and migration.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462554758   1 MSRKGPRAEVCADCSAPDPGWASISRGVLVCDECCSVHRSLGRHISIVKHLRHSAWPPTLLQMVHTLASNGANSIWEHSL 80
Cdd:cd08846     1 MSRKGPRAEVCADCSAPDPGWASINRGVLICDECCSVHRSLGRHISIVKHLRHSAWPPTLLQMVHTLASNGANSIWEHSL 80

                          90       100       110
                  ....*....|....*....|....*....|.
gi 2462554758  81 LDPAQVQSGRRKANPQDKVHPIKSEFIRAKY 111
Cdd:cd08846    81 LDPAQVQSGRRKANPQDKVHPTKSEFIRAKY 111

The GIT subfamily of ADP-ribosylation factor GTPase-activating proteins; The GIT (G-protein coupled receptor kinase-interacting protein) subfamily includes GIT1 and GIT2, which have three ANK repeats, a Spa-homology domain (SHD), a coiled-coil domain and a C-terminal paxillin-binding site (PBS). The GIT1/2 proteins are GTPase-activating proteins that function as an inactivator of Arf signaling, and interact with the PIX/Cool family of Rac/Cdc42 guanine nucleotide exchange factors (GEFs). Unlike other ArfGAPs, GIT and PIX (Pak-interacting exchange factor) proteins are tightly associated to form an oligomeric complex that acts as a scaffold and signal integrator that can be recruited for multiple signaling pathways. The GIT/PIX complex functions as a signaling scaffold by binding to specific protein partners. As a result, the complex is transported to specific cellular locations. For instance, the GIT partners paxillin or integrin-alpha4 (to focal adhesions), piccolo and liprin-alpha (to synapses), and the beta-PIX partner Scribble (to epithelial cell-cell contacts and synapses). Moreover, the GIT/PIT complex functions to integrate signals from multiple GTP-binding protein and protein kinase pathways to regulate the actin cytoskeleton and thus cell polarity, adhesion and migration.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462554758   1 MSRKGPRAEVCADCSAPDPGWASISRGVLVCDECCSVHRSLGRHISIVKHLRHSAWPPTLLQMVHTLASNGANSIWEHSL 80
Cdd:cd08833     1 IRGKSSNARVCADCSAPDPEWASINRGVLICDECCSIHRSLGRHISQVKSLRKDQWPPSLLEMVQTLGNNGANSIWEHSL 80

                          90       100       110
                  ....*....|....*....|....*....|.
gi 2462554758  81 LDPAqvQSGRRKANPQDKVHPIKSEFIRAKY 111
Cdd:cd08833    81 LDPS--QSGKRKPIPPDPVHPTKEEFIKAKY 109

G protein-coupled receptor kinase-interacting protein 1 C term; This domain family is found in eukaryotes, and is approximately 120 amino acids in length. The family is found in association with pfam01412, pfam00023, pfam08518. GIT1 plays an important role in cell adhesion, motility, cytoskeletal remodelling and membrane trafficking. To perform this function, it localizes p21-activated kinase (PAK) and PAK-interactive exchange factor to focal adhesions. Its activation is regulated by interaction between its paxillin-binding C terminal and the LD motifs of paxillin. The C terminal folds into a four helix bundle.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462554758 652 EDVILKTEQVTKNIQELLRAAQEFKHDSFVPCSEKIHLAVTEMASLFPKphscplqRPALEPVRSSLRLLNASAYRLQSE 731
Cdd:pfam12205   2 DNVVRQTELITKAIQELLKAAQEGRHSEFLDCAERIRSAVTEMAALFPK-------SPRSETVREALKALTDAADKLQAE 74

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 2462554758 732 CrKTVPPEPGAPvdfqLLTQQVIQCAYDIAKAAKQLVTITT 772
Cdd:pfam12205  75 C-VSLKASPGPD----DSSQEIITAAYDIAKAAKELVTLFE 110

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 2462554758  10 VCADCSAPDPGWASISRGVLVCDECCSVHRSLGRHISIVKHLRHSAWPPTLLQMVHTLASNGANSIWEHSLLDPaqvqsg 89
Cdd:pfam01412  15 VCADCGAPNPTWASVNLGIFICIDCSGVHRSLGVHISKVRSLTLDTWTDEQLELMKAGGNDRANEFWEANLPPS------ 88

                          90       100       110
                  ....*....|....*....|....*....|
gi 2462554758  90 rrKANPQDKVHPIKSEFIRAKYQMLAFVHK 119
Cdd:pfam01412  89 --YKPPPSSDREKRESFIRAKYVEKKFAKP 116

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 2462554758   3 RKGPRAEVCADCSAPDPGWASISRGVLVCDECCSVHRSLGRHISIVKHLRHSAWPPTLLQMVHTLASNGANSIWEHSLLD 82
Cdd:cd08835     8 LSVPGNAQCCDCGSPDPRWASINLGVTLCIECSGIHRSLGVHVSKVRSLTLDSWEPELLKVMLELGNDVVNRIYEANVPD 87

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 2462554758  83 paqvqSGRRKANPqDKVHPIKSEFIRAKYQMLAFV 117
Cdd:cd08835    88 -----DGSVKPTP-DSSRQEREAWIRAKYVEKKFV 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 2462554758   4 KGPRAEVCADCSAPDPGWASISRGVLVCDECCSVHRSLGRHISIVKHLRHSAWPPTLLQMvhtLASNG---ANSIWEhsl 80
Cdd:cd08832    13 KLPGNNTCADCGAPDPEWASYNLGVFICLDCSGIHRSLGTHISKVKSLRLDNWDDSQVEF---MEENGnekAKAKYE--- 86

                          90       100       110
                  ....*....|....*....|....*....|.
gi 2462554758  81 ldpAQVQSGRRKANPQDkVHPIKSEFIRAKY 111
Cdd:cd08832    87 ---AHVPAFYRRPTPTD-PQVLREQWIRAKY 113

ArfGAP with GTPase domain, ANK repeat and PH domain 1; 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 2462554758  10 VCADCSAPDPGWASISRGVLVCDECCSVHRSLGRHISIVKHLRHSAWPPTLLQMVHTLASNGANSIWEHSLLdpaqvqsG 89
Cdd:cd08854    15 LCVDCGAPNPTWASLNLGALICIECSGIHRNLGTHLSRVRSLDLDDWPRELTLVLTAIGNHMANSIWESCTQ-------G 87

                          90       100
                  ....*....|....*....|...
gi 2462554758  90 RRKANPqDKVHPIKSEFIRAKYQ 112
Cdd:cd08854    88 RTKPAP-DSSREERESWIRAKYE 109

ArfGAP domain of ACAP3 (ArfGAP with Coiled-coil, ANK repeat and PH domains 3); ACAP3 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. It has been shown that ACAP3 positively regulates neurite outgrowth through its GAP activity specific to Arf6 in mouse hippocampal neurons. ACAP1 (centaurin beta1) and ACAP2 centaurin beta2) also 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462554758   6 PRAEVCADCSAPDPGWASISRGVLVCDECCSVHRSLGRHISIVKHLRHSAWPPTLLQMVHTLASNGANSIWEHSLLDpaq 85
Cdd:cd08850    11 AGNDQCCDCGQPDPRWASINLGILLCIECSGIHRSLGVHCSKVRSLTLDSWEPELLKLMCELGNSTVNQIYEAQCEE--- 87

                          90       100       110
                  ....*....|....*....|....*....|
gi 2462554758  86 vqSGRRKANP----QDKVHPIKSEFIRAKY 111
Cdd:cd08850    88 --LGLKKPTAsssrQDKEAWIKAKYVEKKF 115

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 2462554758   1 MSRKGPRAEVCADCSAPDPGWASISRGVLVCDECCSVHRSLGRHISIVKHLRHSAWPPTLLQMVHTLASNGANSIWEHSL 80
Cdd:cd08834     8 EVKRLPGNDVCCDCGSPDPTWLSTNLGILTCIECSGVHRELGVHVSRIQSLTLDNLGTSELLLARNLGNEGFNEIMEANL 87

                          90       100       110
                  ....*....|....*....|....*....|.
gi 2462554758  81 LDpaqvqsgRRKANPQDKVhPIKSEFIRAKY 111
Cdd:cd08834    88 PP-------GYKPTPNSDM-EERKDFIRAKY 110

ArfGAP domain of ACAP2 (ArfGAP with Coiled-coil, ANK repeat and PH domains 2); ACAP2 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 2462554758   6 PRAEVCADCSAPDPGWASISRGVLVCDECCSVHRSLGRHISIVKHLRHSAWPPTLLQMVHTLASNGANSIWEhslldpAQ 85
Cdd:cd08851    11 PGNASCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRIYE------AR 84

                          90       100       110
                  ....*....|....*....|....*....|...
gi 2462554758  86 VQS-GRRKANPQDKVHPIKSeFIRAKYQMLAFV 117
Cdd:cd08851    85 VEKmGAKKPQPGGQRQEKEA-YIRAKYVERKFV 116

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 2462554758   3 RKGPRAEVCADCSAPDPGWASISRGVLVCDECCSVHRSLGRHISIVKHLRHSAWPPTLLQMVHTLASNGANSIWEHSLLD 82
Cdd:cd08848    10 QRLPGNEVCCDCGSPDPTWLSTNLGILTCIECSGIHREMGVHISRIQSLELDKLGTSELLLAKNVGNNSFNDIMEGNLPS 89

                          90       100
                  ....*....|....*....|....*....
gi 2462554758  83 PAQvqsgrrKANPQDKVhPIKSEFIRAKY 111
Cdd:cd08848    90 PSP------KPSPSSDM-TARKEYITAKY 111

GTPase-activating protein that regulates ARFs (ADP-ribosylation factors), involved in ARF-mediated vesicular transport [Intracellular trafficking and secretion];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462554758   3 RKGPRAEVCADCSAPDPGWASISRGVLVCDECCSVHRSLGRHISIVKHLRHSAWPP-TLLQMVHTLASNgANSIWEHSLL 81
Cdd:COG5347    15 KSDSSNKKCADCGAPNPTWASVNLGVFLCIDCAGVHRSLGVHISKVKSLTLDNWTEeELRRMEVGGNSN-ANRFYEKNLL 93

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 2462554758  82 DPAQVqsgrrkanPQDKVH--PIKSEFIRAKYQMLAFV 117
Cdd:COG5347    94 DQLLL--------PIKAKYdsSVAKKYIRKKYELKKFI 123

Ankyrin repeat [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462554758 123 RDDDGVTAkdlskqLHSSVRTGNLETCLRLLSLGAQANFFHPEkGTTPLHVAAKAGQTLQAELLVVYGADPGSPDVNGRT 202
Cdd:COG0666   116 RDKDGETP------LHLAAYNGNLEIVKLLLEAGADVNAQDND-GNTPLHLAAANGNLEIVKLLLEAGADVNARDNDGET 188

                          90
                  ....*....|....*....
gi 2462554758 203 PIDYARQAGHHELAERLVE 221
Cdd:COG0666   189 PLHLAAENGHLEIVKLLLE 207

Arf1 GTPase-activating protein 2/3-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
                  ....*....|....*....|....*....|....*....|....*..
gi 2462554758   3 RKGPRAEVCADCSAPDPGWASISRGVLVCDECCSVHRSLGRHISIVK 49
Cdd:cd08831    10 RSKPENKVCFDCGAKNPTWASVTFGVFLCLDCSGVHRSLGVHISFVR 56

ArfGap with Rho-Gap domain, ANK repeat and PH domain-containing protein 3; 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. ARAP3 possesses a unique dual-specificity GAP activity for Arf6 and RhoA regulated by PI(3,4,5)P3 and a small GTPase Rap1-GTP. The RhoGAP activity of ARAP3 is enhanced by direct binding of Rap1-GTP to the Ras-association (RA) domain. ARAP3 is involved in regulation of cell shape and adhesion.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462554758  11 CADCSAPDPGWASISRGVLVCDECCSVHRSLGRHISIVKHLR--HSAWPPTLLQMVHTLASNGANSIWEHSL-----LDP 83
Cdd:cd17902    16 CADCHASSPDWASINLCVVICKQCAGQHRSLGSGISKVQSLKldTSVWSNEIVQLFIVLGNDRANRFWAARLpaseaLHP 95

                          90       100
                  ....*....|....*....|....*....
gi 2462554758  84 AQVQSGRRkanpqdkvhpiksEFIRAKYQ 112
Cdd:cd17902    96 DATPEQRR-------------EFISRKYR 111

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 2462554758   6 PRAEVCADCSAPDPGWASISRGVLVCDECCSVHRSLGRhISIVKHLRHSAWPPTLLQMVHTLASNGANSIWEhslldpAQ 85
Cdd:cd08843    15 PGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNIPQ-VSKVKSVRLDAWEEAQVEFMASHGNDAARARFE------SK 87

                          90       100
                  ....*....|....*....|....*.
gi 2462554758  86 VQSGRRKANPQDkVHPIKSEFIRAKY 111
Cdd:cd08843    88 VPSFYYRPTPSD-CQLLREQWIRAKY 112

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 2462554758   3 RKGPRAEVCADCSAPDPGWASISRGVLVCDECCSVHRSLGRHISIVKHLRHSAWPPTLLQMVHTLASNGANSIWEHSLld 82
Cdd:cd17900    10 KSRPGNSQCCDCGAPDPTWLSTNLGILTCIECSGIHRELGVRYSRIQSLTLDLLSTSELLLAVSMGNTRFNEVMEATL-- 87

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 2462554758  83 PAQvqsGRRKANPQDKVHPIKsEFIRAKYQMLAFVHK 119
Cdd:cd17900    88 PAH---GGPKPSAESDMGTRK-DYIMAKYVEHRFVRK 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
                  ....*....|....*....|....*....|....*....|....*..
gi 2462554758   3 RKGPRAEVCADCSAPDPGWASISRGVLVCDECCSVHRSLGRHISIVK 49
Cdd:cd09029    14 RAIPTNKACFDCGAKNPSWASITYGVFLCIDCSGVHRSLGVHLSFIR 60

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 2462554758   4 KGPRAEVCADCSAPDPGWASISRGVLVCDECCSVHRSLGRhISIVKHLRHSAWPPTLLQMVHTLASNGANSIWEHSLldP 83
Cdd:cd08844    13 KLPGNSVCADCGAPDPDWASYTLGIFICLNCSGVHRNLPD-ISRVKSIRLDFWEDELVEFMKENGNLKAKAKFEAFV--P 89

                          90       100
                  ....*....|....*....|....*...
gi 2462554758  84 AQVQsgRRKANPQDKvhpIKSEFIRAKY 111
Cdd:cd08844    90 PFYY--RPQANDCDV---LKEQWIRAKY 112

ADP-ribosylation factor GTPase-activating protein AGD10; Provisional

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 2462554758   9 EVCADCSAPDPGWASISRGVLVCDECCSVHRSLGRHISIVKHLRHSAWPPTLLQMV 64
Cdd:PLN03114   23 KICFDCNAKNPTWASVTYGIFLCIDCSAVHRSLGVHISFVRSTNLDSWSSEQLKMM 78

Spa2 homology domain (SHD) of GIT; GIT proteins are signaling integrators with GTPase-activating function which may be involved in the organization of the cytoskeletal matrix assembled at active zones (CAZ). The function of the CAZ might be to define sites of neurotransmitter release. Mutations in the Spa2 homology domain (SHD) domain of GIT1 described here interfere with the association of GIT1 with Piccolo, beta-PIX, and focal adhesion kinase.

                          10        20
                  ....*....|....*....|....*....
gi 2462554758 337 GRQKLARFNAREFATLIIDILSEAKRRQQ 365
Cdd:pfam08518   1 ARQKLARLSNQQFEELVTDVYDELDRRQT 29

Ankyrin repeats (3 copies);

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 2462554758 122 CRDDDGVTAkdlskqLHSSVRTGNLETCLRLLSlgaQANFFHPEKGTTPLHVAAKAGQTLQAELLVVYGADPGSPD 197
Cdd:pfam12796  25 LQDKNGRTA------LHLAAKNGHLEIVKLLLE---HADVNLKDNGRTALHYAARSGHLEIVKLLLEKGADINVKD 91

Helical motif in the GIT family of ADP-ribosylation factor GTPase-activating proteins; Helical motif in the GIT family of ADP-ribosylation factor GTPase-activating proteins, and in yeast Spa2p and Sph1p (CPP; unpublished results). In p95-APP1 the N-terminal GIT motif might be involved in binding PIX.

                           10        20        30
                   ....*....|....*....|....*....|.
gi 2462554758  337 GRQKLARFNAREFATLIIDILSEAKRRQQGK 367
Cdd:smart00555   1 ARQKLARLSDEQFQKLLTDLNDELKRRENEA 31

Spa2 homology domain (SHD) of GIT; GIT proteins are signaling integrators with GTPase-activating function which may be involved in the organization of the cytoskeletal matrix assembled at active zones (CAZ). The function of the CAZ might be to define sites of neurotransmitter release. Mutations in the Spa2 homology domain (SHD) domain of GIT1 described here interfere with the association of GIT1 with Piccolo, beta-PIX, and focal adhesion kinase.

                          10        20
                  ....*....|....*....|.
gi 2462554758 281 SNRLFEELAMDVYDEVDRREN 301
Cdd:pfam08518   9 SNQQFEELVTDVYDELDRRQT 29