Alpha-kinase domain of myosin heavy chain kinase and similar domains; This group is composed of alpha-kinase domains of Dictyostelium discoideum myosin heavy chain kinases A-D (MHCKA, MHCKB, MHCKC, MHCKD), alpha-protein kinase 1 (AK1), and similar proteins. The myosin heavy chain kinases are involved in regulating myosin II filament assembly in Dictyostelium discoideum. They phosphorylate target threonine residues located in the carboxyl-terminal portion of the myosin II heavy chain (MHC) tail, resulting in filament disassembly. The different MHCK isoforms display different spatial regulation, indicating specific roles for each isoform in fine tuning the Dictyostelium actomyosin cytoskeleton. They all contain an alpha-kinase domain as well as WD40 repeats at the C-terminus. AK1 contains an N-terminal Arf-GAP domain and a central alpha-kinase domain. Alpha-kinase is an atypical protein kinase catalytic domain with no detectable similarity to conventional protein serine/threonine kinases. The alpha-kinase family was named after the unique mode of substrate recognition by its initial members, the Dictyostelium heavy chain kinases, which targeted protein sequences that adopt an alpha-helical conformation. More recently, alpha-kinases were found to also target residues in non-helical regions.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 328870521 653 RVIRHRFDAKLGKWIQTATIVITEPTPFAEGAMRKAFRMKDLSAEGPTSQMVAKLFKDPNEDRMVYFKDVEMQTYAREIS 732
Cdd:cd16968    1 RAIKHEFDPETGKWTSTATKVKIDPKPFAEGALREAYHLKDLSAPGPSTLFVAKLSKDPNESRETYFEDVEMQMVCKKWA 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 328870521 733 ERFNAKNPPKKIDFVPAFVMELVERQGRPYCAVEFFIEGKYEKHNNNYGYKNDFDRNTPQAFSHFSYEDSGCQLIVVDIQ 812
Cdd:cd16968   81 EKFNAKNPPKKVEFLPAWVLELVDRPPPPLCGVEPFIEGEYVKHNNNFGYVDEDERNTPQAFSHFTYEASGHQLLVVDIQ 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|..
gi 328870521 813 GVGDVYTDPQIHSADGQGFGKGNLGIEGIKRFFSTHQCNPIC 854
Cdd:cd16968  161 GVGDLYTDPQIHTIDGKGFGKGNLGQKGIEKFLETHKCNAIC 202

Alpha-kinase domain of myosin heavy chain kinase and similar domains; This group is composed of alpha-kinase domains of Dictyostelium discoideum myosin heavy chain kinases A-D (MHCKA, MHCKB, MHCKC, MHCKD), alpha-protein kinase 1 (AK1), and similar proteins. The myosin heavy chain kinases are involved in regulating myosin II filament assembly in Dictyostelium discoideum. They phosphorylate target threonine residues located in the carboxyl-terminal portion of the myosin II heavy chain (MHC) tail, resulting in filament disassembly. The different MHCK isoforms display different spatial regulation, indicating specific roles for each isoform in fine tuning the Dictyostelium actomyosin cytoskeleton. They all contain an alpha-kinase domain as well as WD40 repeats at the C-terminus. AK1 contains an N-terminal Arf-GAP domain and a central alpha-kinase domain. Alpha-kinase is an atypical protein kinase catalytic domain with no detectable similarity to conventional protein serine/threonine kinases. The alpha-kinase family was named after the unique mode of substrate recognition by its initial members, the Dictyostelium heavy chain kinases, which targeted protein sequences that adopt an alpha-helical conformation. More recently, alpha-kinases were found to also target residues in non-helical regions.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 328870521 653 RVIRHRFDAKLGKWIQTATIVITEPTPFAEGAMRKAFRMKDLSAEGPTSQMVAKLFKDPNEDRMVYFKDVEMQTYAREIS 732
Cdd:cd16968    1 RAIKHEFDPETGKWTSTATKVKIDPKPFAEGALREAYHLKDLSAPGPSTLFVAKLSKDPNESRETYFEDVEMQMVCKKWA 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 328870521 733 ERFNAKNPPKKIDFVPAFVMELVERQGRPYCAVEFFIEGKYEKHNNNYGYKNDFDRNTPQAFSHFSYEDSGCQLIVVDIQ 812
Cdd:cd16968   81 EKFNAKNPPKKVEFLPAWVLELVDRPPPPLCGVEPFIEGEYVKHNNNFGYVDEDERNTPQAFSHFTYEASGHQLLVVDIQ 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|..
gi 328870521 813 GVGDVYTDPQIHSADGQGFGKGNLGIEGIKRFFSTHQCNPIC 854
Cdd:cd16968  161 GVGDLYTDPQIHTIDGKGFGKGNLGQKGIEKFLETHKCNAIC 202

Alpha-kinase family; This family is a novel family of eukaryotic protein kinase catalytic domains, which have no detectable similarity to conventional kinases. The family contains myosin heavy chain kinases and Elongation Factor-2 kinase and a bifunctional ion channel. This family is known as the alpha-kinase family. The structure of the kinase domain revealed unexpected similarity to eukaryotic protein kinases in the catalytic core as well as to metabolic enzymes with ATP-grasp domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 328870521  681 AEGAMRKAFRMKDLSAEGPTSQMVAKLFKDPNE--DRMVYFKDVEMQTYAREISERFNA------KNPPKKIDFVPAFVM 752
Cdd:pfam02816   1 AEGAMRKAFKAKVDPGDESGQNYVAKEFKKIVYgvELEYYFEDAQSQALAKELAEEFNAearaleNFPPKKIEFIPPYVV 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 328870521  753 ELVERQGRPYCAVEFFIEGKYEKHNNNYGYKNDFD---RNTPQAFSHFSYEDSGCQLIVVDIQGVGDVYTDPQIHSADGQ 829
Cdd:pfam02816  81 ELDPANGKPYYLVEPFLEGNFVKYNSNTGFVSEEDdelEQTMQAFSHFTYERSGGQLLVCDLQGVGNLLTDPAIHTKDGK 160

                         170       180
                  ....*....|....*....|....*
gi 328870521  830 GFGKGNLGIEGIKRFFSTHQCNPIC 854
Cdd:pfam02816 161 RFGDTNLGEEGIASFFSTHKCNKIC 185

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
                  ....*....|....*....|....*....|....*....|.
gi 328870521   10 ALIRSLFLDANNKQCAECNSLNVPYVCVKLGIFICPTCAHF 50
Cdd:pfam01412   2 RVLRELLKLPGNKVCADCGAPNPTWASVNLGIFICIDCSGV 42

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

                         10        20        30
                 ....*....|....*....|....*....|.
gi 328870521  18 DANNKQCAECNSLNVPYVCVKLGIFICPTCA 48
Cdd:COG5347   17 DSSNKKCADCGAPNPTWASVNLGVFLCIDCA 47

Alpha-kinase domain of myosin heavy chain kinase and similar domains; This group is composed of alpha-kinase domains of Dictyostelium discoideum myosin heavy chain kinases A-D (MHCKA, MHCKB, MHCKC, MHCKD), alpha-protein kinase 1 (AK1), and similar proteins. The myosin heavy chain kinases are involved in regulating myosin II filament assembly in Dictyostelium discoideum. They phosphorylate target threonine residues located in the carboxyl-terminal portion of the myosin II heavy chain (MHC) tail, resulting in filament disassembly. The different MHCK isoforms display different spatial regulation, indicating specific roles for each isoform in fine tuning the Dictyostelium actomyosin cytoskeleton. They all contain an alpha-kinase domain as well as WD40 repeats at the C-terminus. AK1 contains an N-terminal Arf-GAP domain and a central alpha-kinase domain. Alpha-kinase is an atypical protein kinase catalytic domain with no detectable similarity to conventional protein serine/threonine kinases. The alpha-kinase family was named after the unique mode of substrate recognition by its initial members, the Dictyostelium heavy chain kinases, which targeted protein sequences that adopt an alpha-helical conformation. More recently, alpha-kinases were found to also target residues in non-helical regions.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 328870521 653 RVIRHRFDAKLGKWIQTATIVITEPTPFAEGAMRKAFRMKDLSAEGPTSQMVAKLFKDPNEDRMVYFKDVEMQTYAREIS 732
Cdd:cd16968    1 RAIKHEFDPETGKWTSTATKVKIDPKPFAEGALREAYHLKDLSAPGPSTLFVAKLSKDPNESRETYFEDVEMQMVCKKWA 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 328870521 733 ERFNAKNPPKKIDFVPAFVMELVERQGRPYCAVEFFIEGKYEKHNNNYGYKNDFDRNTPQAFSHFSYEDSGCQLIVVDIQ 812
Cdd:cd16968   81 EKFNAKNPPKKVEFLPAWVLELVDRPPPPLCGVEPFIEGEYVKHNNNFGYVDEDERNTPQAFSHFTYEASGHQLLVVDIQ 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|..
gi 328870521 813 GVGDVYTDPQIHSADGQGFGKGNLGIEGIKRFFSTHQCNPIC 854
Cdd:cd16968  161 GVGDLYTDPQIHTIDGKGFGKGNLGQKGIEKFLETHKCNAIC 202

Alpha-kinase domain of eukaryotic elongation factor-2 kinase; Eukaryotic elongation factor-2 kinase (eEF2K) is also called calcium/calmodulin (CaM)-dependent eEF2K. It phosphorylates eukaryotic elongation factor-2 (EEF2) at a single site, leading to its inactivation and inability to bind ribosomes, and slowing down the elongation stage of protein synthesis. It has been linked to many human diseases including cardiovascular conditions (atherosclerosis) and pulmonary arterial hypertension, as well as solid tumors and neurological disorders. eEF2K is an atypical protein kinase containing a CaM binding region, an alpha-kinase catalytic domain, and TPR-like Sel1 repeats at the C-terminus. Alpha-kinase is an atypical protein kinase catalytic domain with no detectable similarity to conventional protein serine/threonine kinases. The alpha-kinase family was named after the unique mode of substrate recognition by its initial members, the Dictyostelium heavy chain kinases, which targeted protein sequences that adopt an alpha-helical conformation. More recently, alpha-kinases were found to also target residues in non-helical regions.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 328870521 651 TERVIRHRFDAKLGKWIQTATIVITEPTPFAEGAMRKAFRMKDLSAEGPTSQ------MVAKLFKDPnEDRMVYFKDVEM 724
Cdd:cd16967    7 TERAVRHRYNAATKKWTKDEVLVKMESKPFARGAMRECYRAKKLSNFSHNQDwkhasnYVAKRYIEP-VDREVYFEDVRL 85

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 328870521 725 QTYAREISERFNAKNPPKKIDFVPAFVMELVERQGRPYCAVEFFIEGKYEKHNNNYGY-KNDFDRNTPQAFSHFSYEDSG 803
Cdd:cd16967   86 QMDAKLWGEEYNRHNPPKKVDIMQMCVLEFVDRPGSPLYHLEHFIEGDYIKYNSNSGFvRDDDIRLTPQAFSHFTFERSG 165

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|.
gi 328870521 804 CQLIVVDIQGVGDVYTDPQIHSADGQGFGKGNLGIEGIKRFFSTHQCNPIC 854
Cdd:cd16967  166 HQLIVVDIQGVGDLYTDPQIHTADGEGYGDGNLGLRGMALFFHSHRCNPIC 216

Alpha kinase family; The alpha kinase family is a novel family of eukaryotic protein kinase catalytic domains, which have no detectable similarity to conventional serine/threonine protein kinases. The family contains myosin heavy chain kinases, elongation factor-2 kinases, and bifunctional ion channel kinases. These kinases are implicated in a large variety of cellular processes such as protein translation, Mg2+/Ca2+ homeostasis, intracellular transport, cell migration, adhesion, and proliferation. The alpha-kinase family was named after the unique mode of substrate recognition by its initial members, the Dictyostelium heavy chain kinases, which targeted protein sequences that adopt an alpha-helical conformation. More recently, alpha-kinases were found to also target residues in non-helical regions.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 328870521 660 DAKLGKWIQTATIV-ITEPTPFAEGAMRKAFRMKDLSAEGptSQMVAKLFK---DPNEDRMVYFKDVEMQTYAREISERF 735
Cdd:cd04515    9 SVTDLKWTTEETTVrVAKKKPFAQGAMREAFKAKDLDSKG--KKYVAKRFKrigDPEENLEDLFDELRMQALAQYLAKEF 86

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 328870521 736 NAK-----NPPKKIDFVPAFVMELVERQ--GRPYCAVEFFIEGKYEKHNNNYGYKNDFD-RNTPQAFSHFSYEDSGCQLI 807
Cdd:cd04515   87 NARaksknLIAPKINFVDPFVVKLGDRDdpGKVVFLVEPFLEGKFVKYNNNNGMVNDEDlGETAQAFSHFTYERSGGQLL 166

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*..
gi 328870521 808 VVDIQGVGDVYTDPQIHSADGQGFGKGNLGIEGIKRFFSTHQCNPIC 854
Cdd:cd04515  167 VTDLQGVGLVLTDPQIHTVDGGGFGLGNLGEEGIKRFFKTHKCNEIC 213

Alpha-kinase domain of alpha-protein kinase 1; Alpha-protein kinase 1 is also called chromosome 4 kinase or lymphocyte alpha-protein kinase (LAK). ALPK1 is implicated in epithelial cell polarity and exocytic vesicular transport towards the apical plasma membrane. It resides on Golgi-derived vesicles where it phosphorylates myosin IA, a motor protein that regulates the delivery of vesicles to the plasma-membrane. It may be associated with inflammation-related diseases such as gout and type 2 diabetes mellitus. ALPK1 contains a C-terminal alpha-kinase domain, an atypical protein kinase catalytic domain with no detectable similarity to conventional protein serine/threonine kinases. The alpha-kinase family was named after the unique mode of substrate recognition by its initial members, the Dictyostelium heavy chain kinases, which targeted protein sequences that adopt an alpha-helical conformation. More recently, alpha-kinases were found to also target residues in non-helical regions.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 328870521 658 RFDAKLGKWIQTATIV-ITEPTPFA-EGAMRKAFRMKDLSAEGPTSQMVAKLFKDPNEDRMvYFKDVEMQTYAR----EI 731
Cdd:cd16969   14 KYSKKSGLWTAQETMVyIGDNLQVGkQGKQRNAFWVHFLHQEETLGRYVGKEYKKPKELQY-HFNDVERQMTAQhyvtEF 92

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 328870521 732 SERFNAKNPPKKIDFVPAFVMELVERQGRPYC-AVEFFIEGKYEKHNNNYGYKNDFDRNTPQ--AFSHFSYEDSGCQLIV 808
Cdd:cd16969   93 NKRLYEQNIPTQIFFIPSVILLILEDKGIKGCvSVEPYMLGEFVKLTNNTTVKKEEYKATDYglAYGHFTYEFSNHQDVV 172

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 328870521 809 VDIQG------VGDVY-TDPQIHSADgQGFGKGNLGIEGIKRFFSTH--QCNPICH 855
Cdd:cd16969  173 VDLQGwvtangKGLTYlTDPQIHSVV-KKSGTTNFGKKGIEYFFNNQhtECNEICR 227

Alpha kinase family; uncharacterized subgroup; The alpha kinase family is a novel family of eukaryotic protein kinase catalytic domains, which have no detectable similarity to conventional serine/threonine protein kinases. The family contains myosin heavy chain kinases, elongation factor-2 kinases, and bifunctional ion channel kinases. These kinases are implicated in a large variety of cellular processes such as protein translation, Mg2+/Ca2+ homeostasis, intracellular transport, cell migration, adhesion, and proliferation. The alpha-kinase family was named after the unique mode of substrate recognition by its initial members, the Dictyostelium heavy chain kinases, which targeted protein sequences that adopt an alpha-helical conformation. More recently, alpha-kinases were found to also target residues in non-helical regions.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 328870521 678 TPFAEGAMRKAFRMKDLSAEGPTSQMVAKLFKDPN--EDRMvYFKDVEMQTYAREISERFNAKN-PPKKIDF----VPAF 750
Cdd:cd17509   34 NPFASGTFRWVYKGFYTSGERKGQACVVKWFKSGHvfEDDY-FDGDIKAVDKALEIVNAFNALNrIDKKIKInvpeVWKF 112

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 328870521 751 VMELVERQGRPYCAVEFFIEGkYEKHNNNYGYKNDFD--RNTPQAFSHFSYEDSGCQLIVVDIQGVGD----VYTDPQIH 824
Cdd:cd17509  113 GDGLTLWWLGRRVLIEPFIEN-YEKFNSNSGWNDDSKgwGEVMQALSHFSYHISGGKYLLCDLQGGVYkneyVLTDPVIL 191

                        170       180       190
                 ....*....|....*....|....*....|
gi 328870521 825 SADGQGFGKGNLGIEGIKRFFSTHQCNPIC 854
Cdd:cd17509  192 SRTGREYGVTDLGPEGIWNFFANHKCNKYC 221

Alpha-kinase domain of channel kinase 1, also called transient receptor potential cation channel subfamily M member 7; Channel kinase 1 (ChaK1), also called transient receptor potential cation channel subfamily M member 7 (TRMP7) or long transient receptor potential channel 7 (LTrpC7), is a fusion protein containing a transmembrane ion pore or channel and a C-terminal alpha-kinase domain, both of which are functional. It is ubiquitously expressed and is a cation-selective channel that preferentially permeates Zn2+, Mg2+, and Ca2+ ions. It is a central regulator of Mg2+ and Ca2+ homeostasis. TRPM7 plays a role in cancer proliferation, stroke, hydrogen peroxide dependent neurodegeneration, and heavy metal toxicity. Alpha-kinase is an atypical protein kinase catalytic domain with no detectable similarity to conventional protein serine/threonine kinases. The alpha-kinase family was named after the unique mode of substrate recognition by its initial members, the Dictyostelium heavy chain kinases, which targeted protein sequences that adopt an alpha-helical conformation. More recently, alpha-kinases were found to also target residues in non-helical regions.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 328870521 713 EDRMVYF--KDVEMQTYAREISERFNAKNPpKKIDFVPAF--VMELVERQGRPYCAVEFFIEGKYEKHNNNYGYK---ND 785
Cdd:cd16971   85 EDTVLHLclREIQQQRAAQKLTFAFNQMKP-KSIPYSPRFleVFLLYCHSAGQWFAVEECMTGEFRKYNNNNGDEiipTN 163

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 328870521 786 FDRNTPQAFSHFSYEDSGCQLIVVDIQGVGDVYTDPQIHSADGQG-----FGKGNLGIEGIKRFFSTHQCNPIC 854
Cdd:cd16971  164 MLEETMLAFSHWTYEYTRGELLVLDLQGVGENLTDPSVIKAGEKRsydmvFGPANLGEDAIKNFRAKHHCNSCC 237

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
                 ....*....|....*....|....*....|....*....|.
gi 328870521  11 LIRSLFLDANNKQCAECNSLNVPYVCVKLGIFICPTCAHFL 51
Cdd:cd08838    3 ILRELLKLPENKRCFDCGQRGPTYVNLTFGTFVCTTCSGIH 43

Alpha-kinase domain of alpha-protein kinase 2; Alpha-protein kinase 2 (ALPK2) is also called heart alpha-protein kinase (HAK). Little functional information is known about ALPK2. In a three-dimensional colonic-crypt model, it has been identified as crucial for luminal apoptosis and expression of DNA repair-related genes, possibly in the transition of normal colonic crypt to adenoma. The ALPK2 gene may also be a novel candidate gene for inherited hypertension in Dahl rats. ALPK2 contains a C-terminal alpha-kinase domain and two immunoglobulin (Ig)-like domains. Alpha-kinase is an atypical protein kinase catalytic domain with no detectable similarity to conventional protein serine/threonine kinases. The alpha-kinase family was named after the unique mode of substrate recognition by its initial members, the Dictyostelium heavy chain kinases, which targeted protein sequences that adopt an alpha-helical conformation. More recently, alpha-kinases were found to also target residues in non-helical regions.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 328870521 672 IVITEPTPFAEGAMRKAFRMKDLSAE----GPTSQMVAKL-----FKDPNEDRMVY------FKDVEMQTYAREISERFN 736
Cdd:cd16974   31 RIATEKLHFGEGMHRKAFRSKVMCGLlpvfLPGHACVLKVhnaiaYGTKNNDELIQknyklaVQECYVQNTAREYAKIYA 110

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 328870521 737 AKNPP-----KKIDFVPAFvmeLVERQGR--PYCAVEFFIEGKYEKHNNNYGYKNDFDRNTPQA------FSHFSYEDSG 803
Cdd:cd16974  111 AEAQPlegfgEVPEIIPIF---LIHRPANniPYATVEEELIGDFVKYSVRDGKEINVLRRDSEAgqkcctFQHWVYQKTD 187

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|...
gi 328870521 804 CQLIVVDIQGVGDVYTDPQIHS-ADG-QGFgKGNLGIEGIKRFFSTHQCNPIC 854
Cdd:cd16974  188 GNLLVTDMQGVGMKLTDVGIATcSKGyKGF-KGNCSVSFIDQFKALHQCNKYC 239

Putative GTP-ase activating proteins for the small GTPase, 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
                   ....*....|....*....|....*....|....*....|
gi 328870521     9 FALIRSLfldANNKQCAECNSLNVPYVCVKLGIFICPTCA 48
Cdd:smart00105   1 LKLLRSI---PGNKKCFDCGAPNPTWASVNLGVFLCIECS 37

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
                 ....*....|....*....|....*...
gi 328870521  21 NKQCAECNSLNVPYVCVKLGIFICPTCA 48
Cdd:cd08832   17 NNTCADCGAPDPEWASYNLGVFICLDCS 44

Arf1 GTPase-activating protein 1; 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 328870521   7 EQFALIRSLfldANNKQCAECNSLNVPYVCVKLGIFICPTCA 48
Cdd:cd08830    3 AVLRELQKL---PGNNRCFDCGAPNPQWASVSYGIFICLECS 41

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.

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gi 328870521  21 NKQCAECNSLNVPYVCVKLGIFICPTCA 48
Cdd:cd08834   15 NDVCCDCGSPDPTWLSTNLGILTCIECS 42