FYVE, RhoGEF and PH domain containing/faciogenital dysplasia proteins 1-4 and similar proteins, N-terminal Pleckstrin homology (PH) domain; In general, FGDs have a RhoGEF (DH) domain, followed by an N-terminal PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activates the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the N-terminal PH domain is involved in intracellular targeting of the DH domain. Mutations in the FGD1 gene are responsible for the X-linked disorder known as faciogenital dysplasia (FGDY). Both FGD1 and FGD3 are targeted by the ubiquitin ligase SCF(FWD1/beta-TrCP) upon phosphorylation of two serine residues in its DSGIDS motif and subsequently degraded by the proteasome. They play different roles to regulate cellular functions, even though their intracellular levels are tightly controlled by the same destruction pathway. FGD4 is one of the genes associated with Charcot-Marie-Tooth neuropathy type 4 (CMT4), a group of progressive motor and sensory axonal and demyelinating neuropathies that are distinguished from other forms of CMT by autosomal recessive inheritance. Those affected have distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity. 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 808357000 443 LLKSGSVQKISSTTEKTEERFIFLFNDLVILASERKMIGVSKYKLRAVFSASHMQVCEGDNLEREHSFYLRGSdgtgpKR 522
Cdd:cd13388    1 LIKEGKILKISARNGDTQERYLFLFNDMLLYCSPRLRLIGQKYKVRARFDVDGMQVLEGDNLETPHTFYVRGK-----QR 75

                         90
                 ....*....|....*....
gi 808357000 523 CVELFTPTQKEKNDWVDSI 541
Cdd:cd13388   76 SLELQASTQEEKAEWVDAI 94

Pleckstrin homology-like domain; The PH-like family includes the PH domain, both the Shc-like and IRS-like PTB domains, the ran-binding domain, the EVH1 domain, a domain in neurobeachin and the third domain of FERM. All of these domains have a PH fold, but lack significant sequence similarity. They are generally involved in targeting to protein to the appropriate cellular location or interacting with a binding partner. This domain family possesses multiple functions including the ability to bind inositol phosphates and to other proteins.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 808357000 671 RFMVVRDdFCMYTYSSEEDICALAMLPLPGCEVKMC------GEKFTFSVRVGARRMYTMTAEDEQTQMKWLAILDLAA 743
Cdd:cd13248   27 RWFVLKD-NCLYYYKDPEEEKALGSILLPSYTISPAppsdeiSRKFAFKAEHANMRTYYFAADTAEEMEQWMNAMSLAA 104

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia proteins 1-4 and similar proteins, N-terminal Pleckstrin homology (PH) domain; In general, FGDs have a RhoGEF (DH) domain, followed by an N-terminal PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activates the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the N-terminal PH domain is involved in intracellular targeting of the DH domain. Mutations in the FGD1 gene are responsible for the X-linked disorder known as faciogenital dysplasia (FGDY). Both FGD1 and FGD3 are targeted by the ubiquitin ligase SCF(FWD1/beta-TrCP) upon phosphorylation of two serine residues in its DSGIDS motif and subsequently degraded by the proteasome. They play different roles to regulate cellular functions, even though their intracellular levels are tightly controlled by the same destruction pathway. FGD4 is one of the genes associated with Charcot-Marie-Tooth neuropathy type 4 (CMT4), a group of progressive motor and sensory axonal and demyelinating neuropathies that are distinguished from other forms of CMT by autosomal recessive inheritance. Those affected have distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity. 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 808357000 443 LLKSGSVQKISSTTEKTEERFIFLFNDLVILASERKMIGVSKYKLRAVFSASHMQVCEGDNLEREHSFYLRGSdgtgpKR 522
Cdd:cd13388    1 LIKEGKILKISARNGDTQERYLFLFNDMLLYCSPRLRLIGQKYKVRARFDVDGMQVLEGDNLETPHTFYVRGK-----QR 75

                         90
                 ....*....|....*....
gi 808357000 523 CVELFTPTQKEKNDWVDSI 541
Cdd:cd13388   76 SLELQASTQEEKAEWVDAI 94

RhoGEF domain; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. It appears that pfam00169 domains invariably occur C-terminal to RhoGEF/DH domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 808357000  234 AAKELVDSEQRYVDKLKLLGDTFRNRLIKEELITNDKITRLLANVSSLYQFHNTHFLPQLLESirdWHTTKRIANVVRKQ 313
Cdd:pfam00621   1 VIKELLQTERSYVRDLEILVEVFLPPNSKPLSESEEEIKTIFSNIEEIYELHRQLLLEELLKE---WISIQRIGDIFLKF 77

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 808357000  314 APFLKMYSEYTNNYDRATKL-FEELKKKKKFADVVKEIEKQAECEGLPLGHHLICPVQRVMRYQLLLQEYKKHLQPSDVD 392
Cdd:pfam00621  78 APGFKVYSTYCSNYPKALKLlKKLLKKNPKFRAFLEELEANPECRGLDLNSFLIKPVQRIPRYPLLLKELLKHTPPDHPD 157

                         170
                  ....*....|....*....
gi 808357000  393 FDDTTVALELVLQAAAHAN 411
Cdd:pfam00621 158 YEDLKKALEAIKEVAKQIN 176

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 808357000   443 LLKSGSVQKISSTTEKT-EERFIFLFNDLVILASERKMigVSKYKLRAVFSASHMQVCEGDN---LEREHSFYLRGSDGt 518
Cdd:smart00233   1 VIKEGWLYKKSGGGKKSwKKRYFVLFNSTLLYYKSKKD--KKSYKPKGSIDLSGCTVREAPDpdsSKKPHCFEIKTSDR- 77

                           90       100
                   ....*....|....*....|....*...
gi 808357000   519 gpkRCVELFTPTQKEKNDWVDSIFSIID 546
Cdd:smart00233  78 ---KTLLLQAESEEEREKWVEALRKAIA 102

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 808357000  443 LLKSGSVQKISSTTEKT-EERFIFLFNDLVILASERKmiGVSKYKLRAVFSASHMQVCE---GDNLEREHSFYLRGSDGT 518
Cdd:pfam00169   1 VVKEGWLLKKGGGKKKSwKKRYFVLFDGSLLYYKDDK--SGKSKEPKGSISLSGCEVVEvvaSDSPKRKFCFELRTGERT 78

                          90       100
                  ....*....|....*....|....*..
gi 808357000  519 GpKRCVELFTPTQKEKNDWVDSIFSII 545
Cdd:pfam00169  79 G-KRTYLLQAESEEERKDWIKAIQSAI 104

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 808357000   651 SGVLHssqIRFRGSLGKLLDRFMVVRDDfCMYTYSSEEDICALA---MLPLPGCEV------KMCGEKFTFSVRVGARRM 721
Cdd:smart00233   4 EGWLY---KKSGGGKKSWKKRYFVLFNS-TLLYYKSKKDKKSYKpkgSIDLSGCTVreapdpDSSKKPHCFEIKTSDRKT 79

                           90       100
                   ....*....|....*....|...
gi 808357000   722 YTMTAEDEQTQMKWLAILDLAAN 744
Cdd:smart00233  80 LLLQAESEEEREKWVEALRKAIA 102

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia proteins 1-4 and similar proteins, N-terminal Pleckstrin homology (PH) domain; In general, FGDs have a RhoGEF (DH) domain, followed by an N-terminal PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activates the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the N-terminal PH domain is involved in intracellular targeting of the DH domain. Mutations in the FGD1 gene are responsible for the X-linked disorder known as faciogenital dysplasia (FGDY). Both FGD1 and FGD3 are targeted by the ubiquitin ligase SCF(FWD1/beta-TrCP) upon phosphorylation of two serine residues in its DSGIDS motif and subsequently degraded by the proteasome. They play different roles to regulate cellular functions, even though their intracellular levels are tightly controlled by the same destruction pathway. FGD4 is one of the genes associated with Charcot-Marie-Tooth neuropathy type 4 (CMT4), a group of progressive motor and sensory axonal and demyelinating neuropathies that are distinguished from other forms of CMT by autosomal recessive inheritance. Those affected have distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity. 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 808357000 443 LLKSGSVQKISSTTEKTEERFIFLFNDLVILASERKMIGVSKYKLRAVFSASHMQVCEGDNLEREHSFYLRGSdgtgpKR 522
Cdd:cd13388    1 LIKEGKILKISARNGDTQERYLFLFNDMLLYCSPRLRLIGQKYKVRARFDVDGMQVLEGDNLETPHTFYVRGK-----QR 75

                         90
                 ....*....|....*....
gi 808357000 523 CVELFTPTQKEKNDWVDSI 541
Cdd:cd13388   76 SLELQASTQEEKAEWVDAI 94

RhoGEF domain; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. It appears that pfam00169 domains invariably occur C-terminal to RhoGEF/DH domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 808357000  234 AAKELVDSEQRYVDKLKLLGDTFRNRLIKEELITNDKITRLLANVSSLYQFHNTHFLPQLLESirdWHTTKRIANVVRKQ 313
Cdd:pfam00621   1 VIKELLQTERSYVRDLEILVEVFLPPNSKPLSESEEEIKTIFSNIEEIYELHRQLLLEELLKE---WISIQRIGDIFLKF 77

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 808357000  314 APFLKMYSEYTNNYDRATKL-FEELKKKKKFADVVKEIEKQAECEGLPLGHHLICPVQRVMRYQLLLQEYKKHLQPSDVD 392
Cdd:pfam00621  78 APGFKVYSTYCSNYPKALKLlKKLLKKNPKFRAFLEELEANPECRGLDLNSFLIKPVQRIPRYPLLLKELLKHTPPDHPD 157

                         170
                  ....*....|....*....
gi 808357000  393 FDDTTVALELVLQAAAHAN 411
Cdd:pfam00621 158 YEDLKKALEAIKEVAKQIN 176

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia family proteins, N-terminal Pleckstrin homology (PH) domain; In general, FGDs have a RhoGEF (DH) domain, followed by an N-terminal PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activates the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the N-terminal PH domain is involved in intracellular targeting of the DH domain. Mutations in the FGD1 gene are responsible for the X-linked disorder known as faciogenital dysplasia (FGDY). 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 808357000 445 KSGSVQKISSTTEKTEERFIFLFNDLVILASERKMIGVSKYKLRAVFSASHMQVCEGDNLEREHSFYLRGSdgtgpKRCV 524
Cdd:cd13328    1 KEGQILKLSAKNGTPQPRYLFLFNDMLLYCVPKLSLVGQKFSVRNRLDVAGMKVREPVNENYPHTFKISGK-----ERSL 75

                         90
                 ....*....|....*..
gi 808357000 525 ELFTPTQKEKNDWVDSI 541
Cdd:cd13328   76 ELQASSAEEKDEWIQAI 92

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia proteins 5 and 6, N-terminal Pleckstrin Homology (PH) domain; FGD5 regulates promotes angiogenesis of vascular endothelial growth factor (VEGF) in vascular endothelial cells, including network formation, permeability, directional movement, and proliferation. The specific function of FGD6 is unknown. In general, FGDs have a RhoGEF (DH) domain, followed by a PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activate the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the PH domain is involved in intracellular targeting of the DH 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 808357000 435 SLVSPGRELLKSGSVQKISSttEKTEERFIFLFNDLVILASERKmiGVSKYKLRAVFSASHMQVCEGDNLEREHSFYLRG 514
Cdd:cd13389    6 NIVKPGRKLIKEGELMKVSR--KEMQPRYFFLFNDCLLYTTPVQ--SSGMLKLNNELPLSGMKVKLPEDEEYSNEFQIIS 81

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 808357000 515 SdgtgpKRCVELFTPTQKEKNDWVDSIFSIIDEAKAHSLTF 555
Cdd:cd13389   82 T-----KRSFTLIASSEEERDEWVKALSRAIEEHTKKQRTF 117

FERM, RhoGEF and pleckstrin domain-containing protein 1 and related proteins Pleckstrin Homology (PH) domain, repeat 1; Members here include FARP1 (also called Chondrocyte-derived ezrin-like protein; PH domain-containing family C member 2), FARP2 (also called FIR/FERM domain including RhoGEF; FGD1-related Cdc42-GEF/FRG), and FARP6 (also called Zinc finger FYVE domain-containing protein 24). They are members of the Dbl family guanine nucleotide exchange factors (GEFs) which are upstream positive regulators of Rho GTPases. Little is known about FARP1 and FARP6, though FARP1 has increased expression in differentiated chondrocytes. FARP2 is thought to regulate neurite remodeling by mediating the signaling pathways from membrane proteins to Rac. It is found in brain, lung, and testis, as well as embryonic hippocampal and cortical neurons. FARP1 and FARP2 are composed of a N-terminal FERM domain, a proline-rich (PR) domain, Dbl-homology (DH), and two C-terminal PH domains. FARP6 is composed of Dbl-homology (DH), and two C-terminal PH domains separated by a FYVE domain. This hierarchy contains the first PH repeat. 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 808357000 436 LVSPGRELLKSGSVQKISSttEKTEERFIFLFNDLVILASeRKMIGVSKYKLRAVFSASHMQVCEGDN-LEREHSFYLRG 514
Cdd:cd01220    1 LVQPGREFIREGCLQKLSK--KGLQQRMFFLFSDVLLYTS-RSPTPSLQFKVHGQLPLRGLMVEESEPeWGVAHCFTIYG 77

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 808357000 515 SDgtgpkRCVELFTPTQKEKNDWVDSIFSIIDEAKAH 551
Cdd:cd01220   78 GN-----RALTVAASSEEEKERWLEDLQRAIDAAKKS 109

FYVE domain like superfamily; FYVE domain is a 60-80 residue double zinc finger motif-containing module named after the four proteins, Fab1, YOTB, Vac1, and EEA1. The canonical FYVE domains are distinguished from other zinc fingers by three signature sequences: an N-terminal WxxD motif (x for any residue), the central basic R(R/K)HHCRxCG patch, and a C-terminal RVC motif, which form a compact phosphatidylinositol 3-phosphate (PtdIns3P, also termed PI3P)-binding site. They are found in many membrane trafficking regulators, including EEA1, Hrs, Vac1p, Vps27p, and FENS-1, which locate to early endosomes, specifically bind PtdIns3P, and play important roles in vesicular traffic and in signal transduction. Some proteins, such as rabphilin-3A and alpha-Rab3-interacting molecules (RIMs), are also involved in membrane trafficking and bind to members of the Rab subfamily of GTP hydrolases. However, they contain FYVE-related domains that are structurally similar to the canonical FYVE domains but lack the three signature sequences. At this point, they may not bind to phosphoinositides. In addition, this superfamily also contains the third group of proteins, caspase-associated ring proteins CARP1 and CARP2. They do not localize to membranes in the cell and are involved in the negative regulation of apoptosis, specifically targeting two initiator caspases, caspase 8 and caspase 10, which are distinguished from other FYVE-type proteins. Moreover, these proteins have an altered sequence in the basic ligand binding patch and lack the WxxD motif that is conserved only in phosphoinositide binding FYVE domains. Thus they constitute a family of unique FYVE-type domains called FYVE-like domains. The FYVE domain is structurally similar to the RING domain and the PHD finger. This superfamily also includes ADDz zinc finger domain, which is a PHD-like zinc finger motif that contains two parts, a C2-C2 and a PHD-like zinc finger.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 808357000 575 HCADCDIEFGFLSRGSKCVKCSRRLCKKCFGRRR-----NESKKHRICDTC 620
Cdd:cd00065    1 RCMLCGKKFSLFRRRHHCRRCGRVFCSKCSSKKLplpsfGSGKPVRVCDSC 51

Phafin2 (also called EAPF, FLJ13187, ZFYVE18 or PLEKHF2) Pleckstrin Homology (PH) domain; Phafin2 is differentially expressed in the liver cancer cell and regulates the structure and function of the endosomes through Rab5-dependent processes. Phafin2 modulates the cell's response to extracellular stimulation by modulating the receptor density on the cell surface. Phafin2 contains a PH domain and a FYVE 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 808357000 422 KVIEVQEQLGNS-ISLVSPGRELLKSGSVQKISSTTEKteERFIFLFNDLVILASErkMIGVSKYKLRAVFSASHMQVCE 500
Cdd:cd01218    8 RIAAVESCFGGSgQPLVKPGRVLVGEGVLTKVCRKKPK--PRQFFLFNDILVYGSI--VINKKKYNKQRIIPLEDVKIED 83

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|..
gi 808357000 501 -GDNLEREHSFYLRGsdgtgPKRCVELFTPTQKEKNDWVDSI 541
Cdd:cd01218   84 lEDTGELKNGWQIIS-----PKKSFVVYAATATEKSEWMDHI 120

Phosphoinositol 3-phosphate binding proteins 1, 2, and 3 pleckstrin homology (PH) domain; PEPP1 (also called PLEKHA4/PH domain-containing family A member 4 and RHOXF1/Rhox homeobox family member 1), and related homologs PEPP2 (also called PLEKHA5/PH domain-containing family A member 5) and PEPP3 (also called PLEKHA6/PH domain-containing family A member 6), have PH domains that interact specifically with PtdIns(3,4)P3. Other proteins that bind PtdIns(3,4)P3 specifically are: TAPP1 (tandem PH-domain-containing protein-1) and TAPP2], PtdIns3P AtPH1, and Ptd- Ins(3,5)P2 (centaurin-beta2). All of these proteins contain at least 5 of the 6 conserved amino acids that make up the putative phosphatidylinositol 3,4,5- trisphosphate-binding motif (PPBM) located at their N-terminus. 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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 808357000 671 RFMVVRDdFCMYTYSSEEDICALAMLPLPGCEVKMC------GEKFTFSVRVGARRMYTMTAEDEQTQMKWLAILDLAA 743
Cdd:cd13248   27 RWFVLKD-NCLYYYKDPEEEKALGSILLPSYTISPAppsdeiSRKFAFKAEHANMRTYYFAADTAEEMEQWMNAMSLAA 104

p63RhoGEF pleckstrin homology (PH) domain, repeat 2; The guanine nucleotide exchange factor p63RhoGEF is an effector of the heterotrimeric G protein, Galphaq and linking Galphaq-coupled receptors (GPCRs) to the activation of RhoA. The Dbl(DH) and PH domains of p63RhoGEF interact with the effector-binding site and the C-terminal region of Galphaq and appear to relieve autoinhibition of the catalytic DH domain by the PH domain. Trio, Duet, and p63RhoGEF are shown to constitute a family of Galphaq effectors that appear to activate RhoA both in vitro and in intact cells. Dbs is a guanine nucleotide exchange factor (GEF), which contains spectrin repeats, a rhoGEF (DH) domain and a PH domain. The Dbs PH domain participates in binding to both the Cdc42 and RhoA GTPases. Trio plays an essential role in regulating the actin cytoskeleton during axonal guidance and branching. Trio is a multidomain signaling protein that contains two RhoGEF(DH)-PH domains in tandem. 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 808357000 452 ISSTTEKTEERFIFLFNDLVILASE---RKMIGVSKYKLRAVFSASHMQVcEGDNLEREHSFYLRGSDGTGPKRCVELFT 528
Cdd:cd13241   29 SAGLLQKGKERRVFLFEQIIIFSEIlgkKTQFSNPGYIYKNHIKVNKMSL-EENVDGDPLRFALKSRDPNNPSETFILQA 107

                         90
                 ....*....|....*...
gi 808357000 529 PTQKEKNDWVDSIFSIID 546
Cdd:cd13241  108 ASPEVRQEWVDTINQILD 125

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 808357000   651 SGVLHssqIRFRGSLGKLLDRFMVVRDDfCMYTYSSEEDICALA---MLPLPGCEV------KMCGEKFTFSVRVGARRM 721
Cdd:smart00233   4 EGWLY---KKSGGGKKSWKKRYFVLFNS-TLLYYKSKKDKKSYKpkgSIDLSGCTVreapdpDSSKKPHCFEIKTSDRKT 79

                           90       100
                   ....*....|....*....|...
gi 808357000   722 YTMTAEDEQTQMKWLAILDLAAN 744
Cdd:smart00233  80 LLLQAESEEEREKWVEALRKAIA 102

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia protein 5, N-terminal Pleckstrin Homology (PH) domain; FGD5 regulates promotes angiogenesis of vascular endothelial growth factor (VEGF) in vascular endothelial cells, including network formation, permeability, directional movement, and proliferation. In general, FGDs have a RhoGEF (DH) domain, followed by a PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activate the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the PH domain is involved in intracellular targeting of the DH 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 808357000 435 SLVSPGRELLKSGSVQKISstTEKTEERFIFLFNDLVILASERKMigvSKYKLRAVFSASHMQVCEGDNLEREHSFYLRG 514
Cdd:cd15792    6 DLLQPGREFVKEGTLMKVS--GKNRHPRHLFLMNDVLLYTYPQKD---GKYRLKNTLAVSGMKVSRPVIEKAQNVLKIEV 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 808357000 515 SDgtgpkRCVELFTPTQKEKNDWVDSIF-SIIDEAKAHSLT 554
Cdd:cd15792   81 SE-----VCLTLSASSCSERDEWYSCLSrTIPDDYKAQNAS 116

FYVE domain found in ankyrin repeat and FYVE domain-containing protein 1 (ANFY1) and similar proteins; ANFY1, also termed ankyrin repeats hooked to a zinc finger motif (Ankhzn), is a novel cytoplasmic protein that belongs to a new group of double zinc finger proteins involved in vesicle or protein transport. It is ubiquitously expressed in a spatiotemporal-specific manner and is located on endosomes. ANFY1 contains an N-terminal coiled-coil region and a BTB/POZ domain, ankyrin repeats in the middle, and a C-terminal FYVE domain.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 808357000 576 CADCDIEFGFLSRGSKCVKCSRRLCKKCFGR-----RRNESKKHRICDTC 620
Cdd:cd15728   10 CYECGVKFGITTRKHHCRHCGRLLCSKCSTKevpiiKFDLNKPVRVCDVC 59

Son of Sevenless (SOS) Pleckstrin homology (PH) domain; SOS is a Ras guanine nucleotide exchange factor. SOS is thought to transmit signals from activated receptor tyrosine kinases to the Ras signaling pathway. SOS contains a histone domain, Dbl-homology (DH), a PH domain, Rem domain, Cdc25 domain, and a Grb2 binding domain. The SOS PH domain binds to phosphatidylinositol-4,5-bisphosphate (PIP2) and phosphatidic acid (PA). SOS is dependent on Ras binding to the allosteric site via its histone domain for both a lower level of activity (Ras GDP) and maximal activity (Ras GTP). The DH domain blocks the allosteric Ras binding site in SOS. The PH domain is closely associated with the DH domain and the action of the DH-PH unit gates a reciprocal interaction between Ras and SOS. The C-terminal proline-rich domain of SOS binds to the adapter protein Grb2 which localizes the Sos protein to the plasma membrane and diminishes the negative effect of the C-terminal domain on the guanine nucleotide exchange activity of the CDC25-homology domain of SOS. 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 808357000 442 ELLKSGSVQKISSTTEKTEeRFIFLFNDLVIL-----ASERKMIGVSKYKLRAVFSASHMQVCE-GDNLEREHSFYLRGS 515
Cdd:cd01261    5 EFIMEGTLGKVGSGKRKTE-RHAFLFDGLLLLcksnrRRTSTGGPKPEYRLKEKFFIRKVEINDlEDTEELKNAFEIVPR 83

                         90       100
                 ....*....|....*....|..
gi 808357000 516 DGTGpkrcVELFTPTQKEKNDW 537
Cdd:cd01261   84 DQPS----VILFAKSAEEKNNW 101

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia proteins 5 and 6 pleckstrin homology (PH) domain, C-terminus; FGD5 regulates promotes angiogenesis of vascular endothelial growth factor (VEGF) in vascular endothelial cells, including network formation, permeability, directional movement, and proliferation. The specific function of FGD6 is unknown. In general, FGDs have a RhoGEF (DH) domain, followed by a PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activate the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the PH domain is involved in intracellular targeting of the DH 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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 808357000 671 RFMVVRDDFCMYTYSSEEDICALAMLPLPGCEVKMCGEKFT------FSVRVGARRMYTMTAEDEQTQMKWLAIL 739
Cdd:cd13237   17 RLWFVLKDKVLYTYKASEDVVALESVPLLGFTVVTIDESFEedeslvFQLLHKGQLPIIFRADDAETAQRWIEAL 91

FYVE domain found in myotubularin-related protein 4 (MTMR4) and similar proteins; MTMR4, also termed FYVE domain-containing dual specificity protein phosphatase 2 (FYVE-DSP2), or zinc finger FYVE domain-containing protein 11, is an dual specificity protein phosphatase that specifically dephosphorylates phosphatidylinositol 3-phosphate (PtdIns3P or PI3P). It is localizes to early endosomes, as well as to Rab11- and Sec15-positive recycling endosomes, and regulates sorting from early endosomes. Moreover, MTMR4 is preferentially associated with and dephosphorylated the activated regulatory Smad proteins (R-Smads) in cytoplasm to keep transforming growth factor (TGF) beta signaling in homeostasis. It also functions as an essential negative modulator for the homeostasis of bone morphogenetic protein (BMP)/decapentaplegic (Dpp) signaling. In addition, MTMR4 acts as a novel interactor of the ubiquitin ligase Nedd4 (neural-precursor-cell-expressed developmentally down-regulated 4) and may play a role in the biological process of muscle breakdown. MTMR4 contains an N-terminal PH-GRAM (PH-G) domain, a MTM phosphatase domain, a coiled-coil region, and a C-terminal FYVE domain.

                         10        20
                 ....*....|....*....|....*....
gi 808357000 575 HCADCDIEFGFLSRGSKCVKCSRRLCKKC 603
Cdd:cd15733    9 HCFGCDCEFWLAKRKHHCRNCGNVFCADC 37