Adaptor protein containing PH domain, PTB domain, and Leucine zipper motif (APPL; also called DCC-interacting protein (DIP)-13alpha) Phosphotyrosine-binding (PTB) domain; APPL interacts with oncoprotein serine/threonine kinase AKT2, tumor suppressor protein DCC (deleted in colorectal cancer), Rab5, GIPC (GAIP-interacting protein, C terminus), human follicle-stimulating hormone receptor (FSHR), and the adiponectin receptors AdipoR1 and AdipoR2. There are two isoforms of human APPL: APPL1 and APPL2, which share about 50% sequence identity. APPL has a BAR and a PH domain near its N terminus, and the two domains are thought to function as a unit (BAR-PH domain). C-terminal to this is a PTB domain. Lipid binding assays show that the BAR, PH, and PTB domains can bind phospholipids. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21699066 489 KSETEDSILHQLFIVRFLGSMEVKSDDHPDVVYETMRQILAARAIHNIFRMTESHLLVTCDCLKLIDPQTQVTRLTFPLP 568
Cdd:cd13158   1 SSEDEDSLLQQLFIVRFLGSMEVKSDRTSEVIYEAMRQVLAARAIHNIFRMTESHLLVTSDCLRLIDPQTQVTRARFPLA 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 21699066 569 CVVLYATHQENKRLFGFVLRTSGGRSESNlSSVCYIFESNNEGEKICDSVGLAKQI 624
Cdd:cd13158  81 DVVQFAAHQENKRLFGFVVRTPEGDGEEP-SFSCYVFESNTEGEKICDAIALAKQI 135

Adaptor protein containing PH domain, PTB domain, and Leucine zipper motif (APPL; also called DCC-interacting protein (DIP)-13alpha) Phosphotyrosine-binding (PTB) domain; APPL interacts with oncoprotein serine/threonine kinase AKT2, tumor suppressor protein DCC (deleted in colorectal cancer), Rab5, GIPC (GAIP-interacting protein, C terminus), human follicle-stimulating hormone receptor (FSHR), and the adiponectin receptors AdipoR1 and AdipoR2. There are two isoforms of human APPL: APPL1 and APPL2, which share about 50% sequence identity. APPL has a BAR and a PH domain near its N terminus, and the two domains are thought to function as a unit (BAR-PH domain). C-terminal to this is a PTB domain. Lipid binding assays show that the BAR, PH, and PTB domains can bind phospholipids. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21699066 489 KSETEDSILHQLFIVRFLGSMEVKSDDHPDVVYETMRQILAARAIHNIFRMTESHLLVTCDCLKLIDPQTQVTRLTFPLP 568
Cdd:cd13158   1 SSEDEDSLLQQLFIVRFLGSMEVKSDRTSEVIYEAMRQVLAARAIHNIFRMTESHLLVTSDCLRLIDPQTQVTRARFPLA 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 21699066 569 CVVLYATHQENKRLFGFVLRTSGGRSESNlSSVCYIFESNNEGEKICDSVGLAKQI 624
Cdd:cd13158  81 DVVQFAAHQENKRLFGFVVRTPEGDGEEP-SFSCYVFESNTEGEKICDAIALAKQI 135

Adaptor protein containing PH domain, PTB domain, and Leucine zipper motif Bin1/amphiphysin/Rvs167 (BAR)-Pleckstrin homology (PH) domain; APPL (also called DCC-interacting protein (DIP)-13alpha) interacts with oncoprotein serine/threonine kinase AKT2, tumor suppressor protein DCC (deleted in colorectal cancer), Rab5, GIPC (GAIP-interacting protein, C terminus), human follicle-stimulating hormone receptor (FSHR), and the adiponectin receptors AdipoR1 and AdipoR2. There are two isoforms of human APPL: APPL1 and APPL2, which share about 50% sequence identity. APPL has a BAR and a PH domain near its N terminus, and the two domains are thought to function as a unit (BAR-PH domain). C-terminal to this is a PTB domain. Lipid binding assays show that the BAR, PH, and PTB domains can bind phospholipids. 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 21699066 252 EDLEVASDPLYLPDPDPTKFPINRNLTRKAGYLNARNKTGLVSSTWDRQFYFTQGGNLMSQARGDVAGGLAMDIDNCSVM 331
Cdd:cd13247   1 EELSSSADYFYEGDPDETQAAPNRNLTQKAGYLFIRSKTGLVTNKWDRTYFFTQGGNLMSQPRDEVAGSLVLDLDNCSVQ 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*
gi 21699066 332 AVDCEDRRYCFQITSFDGKKSSILQAESKKDHEEWICTINNISKQ 376
Cdd:cd13247  81 AADCEDRRNVFQITSPDGKKAIVLQAESKKDYEEWIATINNISQQ 125

Phosphotyrosine interaction domain (PTB/PID);

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21699066   501 FIVRFLGSMEVKSDDHPD------VVYETMRQILAA------RAIHNIFRMTESHLLVTCDCLKLIDPQTQVTRLTFPLP 568
Cdd:pfam00640   1 FAVRYLGSVEVPEERAPDkntrmqQAREAIRRVKAAkinkirGLSGETGPGTKVDLFISTDGLKLLNPDTQELIHDHPLV 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 21699066   569 CVVLYA-THQENKRLFGFVLRtsGGRSESNLssvCYIFESNNEGEKICDSVGLAKQIA 625
Cdd:pfam00640  81 SISFCAdGDPDLMRYFAYIAR--DKATNKFA---CHVFESEDGAQDIAQSIGQAFALA 133

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21699066   280 KAGYLnaRNKTGLVSSTWDRQFYFTQGGNLMSQARGDVAGGLA----MDIDNCSVMAVDCED---RRYCFQI--TSFDGK 350
Cdd:pfam00169   3 KEGWL--LKKGGGKKKSWKKRYFVLFDGSLLYYKDDKSGKSKEpkgsISLSGCEVVEVVASDspkRKFCFELrtGERTGK 80

                          90       100
                  ....*....|....*....|....*
gi 21699066   351 KSSILQAESKKDHEEWICTINNISK 375
Cdd:pfam00169  81 RTYLLQAESEEERKDWIKAIQSAIR 105

The Bin/Amphiphysin/Rvs (BAR) domain of Adaptor protein, Phosphotyrosine interaction, PH domain and Leucine zipper containing proteins; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. Adaptor protein, Phosphotyrosine interaction, PH domain and Leucine zipper containing (APPL) proteins are effectors of the small GTPase Rab5 that function in endosome-mediated signaling. They contain BAR, pleckstrin homology (PH) and phosphotyrosine binding (PTB) domains. They form homo- and hetero-oligomers that are mediated by their BAR domains, and are localized to cytoplasmic membranes. Vertebrates contain two APPL proteins, APPL1 and APPL2. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21699066  20 RSLLGVFEEDATAISNYMNQLYQAMHRIYDAQNELSAATHLTSKLLKEYEKQRFPLGGDDEVMSSTLQQFSKVIDELSSC 99
Cdd:cd07601   1 RSLLNVFEEDALQLSSYMNQLLQACKRVYDAQNELKSATQALSKKLGEYEKQKFELGRDDEILVSTLKQFSKVVDELSTM 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21699066 100 HAVLSTQLADAMMFPISQFKERDLKEILTLKEVFQIASNDHDAAINRYSRLSKKRENDKVKYEVTEDVYTSRKKQHQTMM 179
Cdd:cd07601  81 HSTLSSQLADTVLHPISQFMESDLAEIMTLKELFKAASNDHDGVLSKYSRLSKKRENTKVKIEVNDEVYACRKKQHQTAM 160

                       170       180       190       200       210
                ....*....|....*....|....*....|....*....|....*....|....*
gi 21699066 180 HYFCALNTLQYKKKIALLEPLLGYMQAQISFFKMGSENLNGQLEEFLANIGTSVQ 234
Cdd:cd07601 161 NYYCALNLLQYKKTTALLEPMIGYLQAQIAFFKMGPEMFTRQTEEFLSDINTSVQ 215

Adaptor protein containing PH domain, PTB domain, and Leucine zipper motif (APPL; also called DCC-interacting protein (DIP)-13alpha) Phosphotyrosine-binding (PTB) domain; APPL interacts with oncoprotein serine/threonine kinase AKT2, tumor suppressor protein DCC (deleted in colorectal cancer), Rab5, GIPC (GAIP-interacting protein, C terminus), human follicle-stimulating hormone receptor (FSHR), and the adiponectin receptors AdipoR1 and AdipoR2. There are two isoforms of human APPL: APPL1 and APPL2, which share about 50% sequence identity. APPL has a BAR and a PH domain near its N terminus, and the two domains are thought to function as a unit (BAR-PH domain). C-terminal to this is a PTB domain. Lipid binding assays show that the BAR, PH, and PTB domains can bind phospholipids. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21699066 489 KSETEDSILHQLFIVRFLGSMEVKSDDHPDVVYETMRQILAARAIHNIFRMTESHLLVTCDCLKLIDPQTQVTRLTFPLP 568
Cdd:cd13158   1 SSEDEDSLLQQLFIVRFLGSMEVKSDRTSEVIYEAMRQVLAARAIHNIFRMTESHLLVTSDCLRLIDPQTQVTRARFPLA 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 21699066 569 CVVLYATHQENKRLFGFVLRTSGGRSESNlSSVCYIFESNNEGEKICDSVGLAKQI 624
Cdd:cd13158  81 DVVQFAAHQENKRLFGFVVRTPEGDGEEP-SFSCYVFESNTEGEKICDAIALAKQI 135

Adaptor protein containing PH domain, PTB domain, and Leucine zipper motif Bin1/amphiphysin/Rvs167 (BAR)-Pleckstrin homology (PH) domain; APPL (also called DCC-interacting protein (DIP)-13alpha) interacts with oncoprotein serine/threonine kinase AKT2, tumor suppressor protein DCC (deleted in colorectal cancer), Rab5, GIPC (GAIP-interacting protein, C terminus), human follicle-stimulating hormone receptor (FSHR), and the adiponectin receptors AdipoR1 and AdipoR2. There are two isoforms of human APPL: APPL1 and APPL2, which share about 50% sequence identity. APPL has a BAR and a PH domain near its N terminus, and the two domains are thought to function as a unit (BAR-PH domain). C-terminal to this is a PTB domain. Lipid binding assays show that the BAR, PH, and PTB domains can bind phospholipids. 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 21699066 252 EDLEVASDPLYLPDPDPTKFPINRNLTRKAGYLNARNKTGLVSSTWDRQFYFTQGGNLMSQARGDVAGGLAMDIDNCSVM 331
Cdd:cd13247   1 EELSSSADYFYEGDPDETQAAPNRNLTQKAGYLFIRSKTGLVTNKWDRTYFFTQGGNLMSQPRDEVAGSLVLDLDNCSVQ 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*
gi 21699066 332 AVDCEDRRYCFQITSFDGKKSSILQAESKKDHEEWICTINNISKQ 376
Cdd:cd13247  81 AADCEDRRNVFQITSPDGKKAIVLQAESKKDYEEWIATINNISQQ 125

Phosphotyrosine-binding (PTB) PH-like fold; PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to bind peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21699066 499 QLFIVRFLGSMEVKSDDHPDVVYETMRqILAARAIHNIFRMTESHLLVTCDCLKLIDPQTQVTRLTFPLPCVVLYATHQE 578
Cdd:cd00934   1 ASFQVKYLGSVEVGSSRGVDVVEEALK-ALAAALKSSKRKPGPVLLEVSSKGVKLLDLDTKELLLRHPLHRISYCGRDPD 79

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*
gi 21699066 579 NKRLFGFVLRTSGGRsesnlSSVCYIFESNN--EGEKICDSVGLA 621
Cdd:cd00934  80 NPNVFAFIAGEEGGS-----GFRCHVFQCEDeeEAEEILQAIGQA 119

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 21699066 280 KAGYLNARNKTGLvsSTWDRQFYFTQGGNLMSQARGDVAGGLAM--DIDNCSVMAVDCEDRRYCFQITSfdGKKSSILQA 357
Cdd:cd13250   1 KEGYLFKRSSNAF--KTWKRRWFSLQNGQLYYQKRDKKDEPTVMveDLRLCTVKPTEDSDRRFCFEVIS--PTKSYMLQA 76

                        90       100
                ....*....|....*....|
gi 21699066 358 ESKKDHEEWICTINN-ISKQ 376
Cdd:cd13250  77 ESEEDRQAWIQAIQSaIASA 96

The Bin/Amphiphysin/Rvs (BAR) domain of the plant protein SCARFACE (SFC); BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions including organelle biogenesis, membrane trafficking or remodeling, and cell division and migration. The plant protein SCARFACE (SFC), also called VAscular Network 3 (VAN3), is a plant ACAP (ArfGAP with Coiled-coil, ANK repeat and PH domain containing protein), an Arf GTPase Activating Protein (GAP) that plays a role in the trafficking of auxin efflux regulators from the plasma membrane to the endosome. It is required for the normal vein patterning in leaves. SCF contains an N-terminal BAR domain, followed by a Pleckstrin Homology (PH) domain, an Arf GAP domain, and C-terminal ankyrin (ANK) repeats. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21699066  27 EEDATAISNYMNQLYQAMHRIYDAQNELSAATHLTSKLLKEyekqrFPLGGDDEVMSST----LQQFSKVIDELSSCHAV 102
Cdd:cd07606   7 EGSADELRDRSLKLYKGCRKYRDALGEAYDGDSAFAESLEE-----FGGGHDDPISVAVggpvMTKFTSALREIGSYKEV 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21699066 103 LSTQLADAMMFPISQFKERDLKEILTLKEVFQIASNDHDAAINRYSRLSKKRENDKVKyEVTEDVYTSRKKQHQTMMHYF 182
Cdd:cd07606  82 LRSQVEHMLNDRLAQFADTDLQEVKDARRRFDKASLDYEQARSKFLSLTKDAKPEILA-AAEEDLGTTRSAFETARFDLM 160

                       170       180       190       200
                ....*....|....*....|....*....|....*....|...
gi 21699066 183 CALNTLQYKKKIALLEPLLGYMQAQISFFKMGSENLnGQLEEF 225
Cdd:cd07606 161 NRLHAADARKRVEFLERLSGSMDAHLAFFKSGYELL-RQLEPY 202

The Bin/Amphiphysin/Rvs (BAR) domain of ArfGAP with Coiled-coil, ANK repeat and PH domain containing protein 3; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. ACAP3 (ArfGAP with Coiled-coil, ANK repeat and PH domain containing protein 3), also called centaurin beta-5, is presumed to be an Arf GTPase activating protein (GAP) based on its similarity to the Arf6-specific GAPs ACAP1 and ACAP2. The specific function of ACAP3 is still unknown. ACAP3 contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain, and C-terminal ankyrin (ANK) repeats. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21699066  79 DEVMSSTLQQFSKVIDELSSCHAVLSTQLADAMMFPISQFKERDLKEILTLKEVFQIASNDHDAAINRYSRLSKKRENDK 158
Cdd:cd07637  56 DEMISECLDKFGDSLQEMVNYHMILFDQAQRSVRQQLHSFVKEDVRKFKETKKQFDKVREDLEIALVKNAQAPRHKPHEV 135

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 21699066 159 vkYEVTEDVYTSRKKQHQTMMHYFCALNTLQYKKKIALLEPLLGYMQAQISFFKMGSENLNgQLEEFL 226
Cdd:cd07637 136 --EEATSTLTITRKCFRHLALDYVLQINVLQAKKKFEILDSMLSFMHAQYTFFQQGYSLLH-ELDPYM 200

The Bin/Amphiphysin/Rvs (BAR) domain of Rho GTPase activating protein 10-like; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. This group is composed of uncharacterized proteins called Rho GTPase activating protein (GAP) 10-like. GAP10-like may be a GAP with activity towards RhoA and Cdc42. Similar to GRAF and GRAF2, it contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions. The BAR domains of the related proteins GRAF and OPHN1, directly interact with their Rho GAP domains and inhibit theiractivity. The autoinhibited proteins are capable of binding membranes and tubulating liposomes, showing that the membrane-tubulation and GAP-inhibitory functions of the BAR domain can occur simultaneously.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21699066  20 RSLLGVFEEDATAISNYMNQLYQAMHRIYDAQNELSAATHLTSKLLKEYEkqrFPLGGD----DEV-MSSTLQQFSKVID 94
Cdd:cd07634   1 RERLQCHEIELERTNKFIKELIKDGSLLIGALRNLSMAVQKFSQSLQDFQ---FECIGDaetdDEIsIAQSLKEFARLLI 77

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21699066  95 ELSSCHAVLSTQLADAMMFPISQFKERDLKEILTLKEVFQIASNDHDAAINRYSRLSKKRENDKVKYEVTEdVYTSRKKQ 174
Cdd:cd07634  78 AVEEERRRLIQNANDVLIAPLEKFRKEQIGAAKDGKKKFDKESEKYYSILEKHLNLSAKKKESHLQRADTQ-IDREHQNF 156

                       170       180       190       200
                ....*....|....*....|....*....|....*....|..
gi 21699066 175 HQTMMHYFCALNTLQYKKKIALLEPLLGYMQAQISFFKMGSE 216
Cdd:cd07634 157 YEASLEYVFKIQEVQEKKKFEFVEPLLAFLQGLFTFYHEGYE 198

Pleckstrin homology (PH) domain; 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 21699066 280 KAGYLnaRNKTGLVSSTW-DRQFYFTQGGNLMSQARGDVAGGLAMDID---NCSVMAVDCEDRRYCFQITSFDGkKSSIL 355
Cdd:cd00821   1 KEGYL--LKRGGGGLKSWkKRWFVLFEGVLLYYKSKKDSSYKPKGSIPlsgILEVEEVSPKERPHCFELVTPDG-RTYYL 77

                        90
                ....*....|....*
gi 21699066 356 QAESKKDHEEWICTI 370
Cdd:cd00821  78 QADSEEERQEWLKAL 92

Cell death protein 6 homolog (CED-6/GULP1) Phosphotyrosine-binding (PTB) domain; CED6 (also known as GULP1: engulfment adaptor PTB domain containing 1) is an adaptor protein involved in the specific recognition and engulfment of apoptotic cells. CED6 has been shown to interact with the cytoplasmic tail of another protein involved in the engulfment of apoptotic cells, CED1. CED6 has a C-terminal PTB domain, which can bind to NPXY motifs. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd is part of the Dab-like subgroup.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21699066 498 HQLFIVRFLGSMEVKSDDHPDVVYETMRQILAARAIHNI--FRMTESHLLVTCDCLKLIDPQTQVTRLTFPLPCVVLYAT 575
Cdd:cd01273  11 HVAYLVKFLGCTEVEQPKGTEVVKEAIRKLKFARQLKKSegAKLPKVELQISIDGVKIQDPKTKVIMHQFPLHRISFCAD 90

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
gi 21699066 576 HQENKRLFGFVLRTSGGRSESnlssvCYIFESNNEGEKICDSVGLAKQIA 625
Cdd:cd01273  91 DKTDKRIFSFIAKDSESEKHL-----CFVFDSEKLAEEITLTIGQAFDLA 135

The Bin/Amphiphysin/Rvs (BAR) domain of ArfGAP with SH3 domain, ANK repeat and PH domain containing protein 2; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. ASAP2 (ArfGAP with SH3 domain, ANK repeat and PH domain containing protein 2) is also known as DDEF2 (Development and Differentiation Enhancing Factor 2), AMAP2, centaurin beta-3, or PAG3. ASAP2 mediates the functions of Arf GTPases vial dual mechanisms: it exhibits GTPase activating protein (GAP) activity towards class I (Arf1) and II (Arf5) Arfs; and binds class III Arfs (GTP-Arf6) stably without GAP activity. It binds paxillin and is implicated in Fcgamma receptor-mediated phagocytosis in macrophages and in cell migration. ASAP2 contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain, ankyrin (ANK) repeats, and a C-terminal SH3 domain. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions. The BAR domain of the related protein ASAP1 mediates membrane bending, is essential for function, and autoinhibits GAP activity by interacting with the PH and/or Arf GAP domains.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21699066  78 DDEVMSSTLQQFSKVIDELSSCHAVLSTQLADAMMFPISQFKERDLKEIL-TLKEVFQIASNDHDAAINRYSRlsKKREN 156
Cdd:cd07642  57 DDPDLGSAFLKFSVFTKELTALFKNLVQNMNNIITFPLDSLLKGDLKGVKgDLKKPFDKAWKDYETKVTKIEK--EKKEH 134

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21699066 157 DKVK---------YEVTEDVYTSRKKQHQTMMHYFCALNTLQYKKKIALLEPLLGYMQAQISFFKMG---SENLNGQLEE 224
Cdd:cd07642 135 AKMHgmirteisgAEIAEEMEKERRFFQLQMCEYLLKVNEIKIKKGVDLLQNLIKYFHAQCNFFQDGlkaVETLKPSIEK 214

                .
gi 21699066 225 F 225
Cdd:cd07642 215 L 215

The Bin/Amphiphysin/Rvs (BAR) domain of GTPase Regulator Associated with Focal adhesion kinase; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. GTPase Regulator Associated with Focal adhesion kinase (GRAF), also called Rho GTPase activating protein 26 (ARHGAP26), is a GAP with activity towards RhoA and Cdc42 and is only weakly active towards Rac1. It influences Rho-mediated cytoskeletal rearrangements and binds focal adhesion kinase (FAK), which is a critical component of integrin signaling. GRAF contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions. The BAR domain of GRAF directly interacts with its Rho GAP domain and inhibits its activity. Autoinhibited GRAF is capable of binding membranes and tubulating liposomes, showing that the membrane-tubulation and GAP-inhibitory functions of the BAR domain can occur simultaneously.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21699066  20 RSLLGVFEEDATAISNYMNQLYQAMHRIYDAQNELSAATHLTSKLLKEYekqRFPLGGD----DEV-MSSTLQQFSKVID 94
Cdd:cd07636   1 RERLKSHEAELDKTNKFIKELIKDGKSLIAALKNLSSAKRKFADSLNEF---KFQCIGDaetdDEIcIARSLQEFAAVLR 77

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21699066  95 ELSSCHAVLSTQLADAMMFPISQFKERDLKEILTLKEVFQIASNDHDAAINRYSRLSKKRENDKVkYEVTEDVYTSRKKQ 174
Cdd:cd07636  78 NLEDERTRMIENASEVLITPLEKFRKEQIGAAKEAKKKYDKETEKYCAVLEKHLNLSSKKKESQL-HEADSQVDLVRQHF 156

                       170       180       190       200
                ....*....|....*....|....*....|....*....|..
gi 21699066 175 HQTMMHYFCALNTLQYKKKIALLEPLLGYMQAQISFFKMGSE 216
Cdd:cd07636 157 YEVSLEYVFKVQEVQERKMFEFVEPLLAFLQGLFTFYHHGYE 198

Sesquipedalian family Pleckstrin homology (PH) domain; The sesquipedalian family has 2 mammalian members: Ses1 and Ses2, which are also callled 7 kDa inositol polyphosphate phosphatase-interacting protein 1 and 2. They play a role in endocytic trafficking and are required for receptor recycling from endosomes, both to the trans-Golgi network and the plasma membrane. Members of this family form homodimers and heterodimers. Sesquipedalian interacts with inositol polyphosphate 5-phosphatase OCRL-1 (INPP5F) also known as Lowe oculocerebrorenal syndrome protein, a phosphatase enzyme that is involved in actin polymerization and is found in the trans-Golgi network and INPP5B. Sesquipedalian contains a single PH domain. 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 21699066 280 KAGYLNarnKTGLVSSTWDRQfYFTQGGNLM----SQARGDVAGGLAMDidNCSVMAVDCEDRrYCFQITsFDGK--KSS 353
Cdd:cd13288  10 KEGYLW---KKGERNTSYQKR-WFVLKGNLLfyfeKKGDREPLGVIVLE--GCTVELAEDAEP-YAFAIR-FDGPgaRSY 81

                        90
                ....*....|....
gi 21699066 354 ILQAESKKDHEEWI 367
Cdd:cd13288  82 VLAAENQEDMESWM 95

The Bin/Amphiphysin/Rvs (BAR) domain of ArfGAP with Coiled-coil, ANK repeat and PH domain containing protein 1; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. ACAP1 (ArfGAP with Coiled-coil, ANK repeat and PH domain containing protein 1), also called centaurin beta-1, is an Arf6-specific GTPase activating protein (GAP) which mediates Arf6 signaling. Arf6 is involved in the regulation of endocytosis, phagocytosis, cell adhesion and migration. ACAP1 also participates in the cargo sorting and recycling of the transferrin receptor and integrin beta1. It may also play a role in innate immune responses. ACAP1 contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain, and C-terminal ankyrin (ANK) repeats. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21699066  75 LGGDDEVMSSTLQQFSKVIDELSSCHAVLSTQLADAMMFPISQFKERDLKEILTLKEVFQIASNDHDAAINRYSRLSKKR 154
Cdd:cd07639  52 HGPKDPMMAECLEKFSDGLNHILDSHAELLEATQFSFKQQLQLLVKEDLRGFRDARKEFERGAESLEAALQHNAETPRRK 131

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 21699066 155 ENDKvkYEVTEDVYTSRKKQHQTMMHYFCALNTLQYKKKIALLEPLLGYMQAQISFFKMGSENL 218
Cdd:cd07639 132 AQEV--EEAAAALLGARATFRDRALDYALQINVIEDKKKFDILEFMLQLMEAQASFFQQGHEAL 193

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 21699066    278 TRKAGYLnaRNKTGLVSSTWDRQFYFTQGGNLM----SQARGDVAGGLAMDIDNCSVMAVDCED---RRYCFQITSFDGK 350
Cdd:smart00233   1 VIKEGWL--YKKSGGGKKSWKKRYFVLFNSTLLyyksKKDKKSYKPKGSIDLSGCTVREAPDPDsskKPHCFEIKTSDRK 78

                           90       100
                   ....*....|....*....|....*
gi 21699066    351 kSSILQAESKKDHEEWICTINNISK 375
Cdd:smart00233  79 -TLLLQAESEEEREKWVEALRKAIA 102

Pleckstrin homology (PH) domain containing, family H (with MyTH4 domain) members 1 and 2 (PLEKHH1) PH domain, repeat 1; PLEKHH1 and PLEKHH2 (also called PLEKHH1L) are thought to function in phospholipid binding and signal transduction. There are 3 Human PLEKHH genes: PLEKHH1, PLEKHH2, and PLEKHH3. There are many isoforms, the longest of which contain a FERM domain, a MyTH4 domain, two PH domains, a peroximal domain, a vacuolar domain, and a coiled coil stretch. The FERM domain has a cloverleaf tripart structure (FERM_N, FERM_M, FERM_C/N, alpha-, and C-lobe/A-lobe, B-lobe, C-lobe/F1, F2, F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. 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 21699066 280 KAGYLNarnKTGLVSSTWDRQFYFTQGGNLMS-QARGDVA----GGLAMDiDNCSVMavdCEDRRYCFQITSfdGKKSSI 354
Cdd:cd13282   1 KAGYLT---KLGGKVKTWKRRWFVLKNGELFYyKSPNDVIrkpqGQIALD-GSCEIA---RAEGAQTFEIVT--EKRTYY 71

                        90
                ....*....|....*....
gi 21699066 355 LQAESKKDHEEWICTINNI 373
Cdd:cd13282  72 LTADSENDLDEWIRVIQNV 90

Dedicator of cytokinesis-D subfamily Pleckstrin homology (PH) domain; DOCK-D subfamily (also called Zizimin subfamily) consists of Dock9/Zizimin1, Dock10/Zizimin3, and Dock11/Zizimin2. DOCK-D has a N-terminal DUF3398 domain, a PH-like domain, a Dock Homology Region 1, DHR1 (also called CZH1), a C2 domain, and a C-terminal DHR2 domain (also called CZH2). Zizimin1 is enriched in the brain, lung, and kidney; zizimin2 is found in B and T lymphocytes, and zizimin3 is enriched in brain, lung, spleen and thymus. Zizimin1 functions in autoinhibition and membrane targeting. Zizimin2 is an immune-related and age-regulated guanine nucleotide exchange factor, which facilitates filopodial formation through activation of Cdc42, which results in activation of cell migration. No function has been determined for Zizimin3 to date. The N-terminal half of zizimin1 binds to the GEF domain through three distinct areas, including CZH1, to inhibit the interaction with Cdc42. In addition its PH domain binds phosphoinositides and mediates zizimin1 membrane targeting. DOCK is a family of proteins involved in intracellular signalling networks. They act as guanine nucleotide exchange factors for small G proteins of the Rho family, such as Rac and Cdc42. There are 4 subfamilies of DOCK family proteins based on their sequence homology: A-D. 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
                ....*....|....*....|....*....|....*....
gi 21699066 338 RRYCFQItSFDGKKSSILQAESKKDHEEWICTINNISKQ 376
Cdd:cd13267  78 RKFCFEL-RMQDKKSYVLAAESEAEMDEWISKLNKILQS 115