Fermitin family pleckstrin homology (PH) domain; Fermitin functions as a mediator of integrin inside-out signalling. The recruitment of Fermitin proteins and Talin to the membrane mediates the terminal event of integrin signalling, via interaction with integrin beta subunits. Fermatin has FERM domain interrupted with a pleckstrin homology (PH) domain. Fermitin family homologs (Fermt1, 2, and 3, also known as Kindlins) are each encoded by a different gene. In mammalian studies, Fermt1 is generally expressed in epithelial cells, Fermt2 is expressed inmuscle tissues, and Fermt3 is expressed in hematopoietic lineages. Specifically Fermt2 is expressed in smooth and striated muscle tissues in mice and in the somites (a trunk muscle precursor) and neural crest in Xenopus embryos. As such it has been proposed that Fermt2 plays a role in cardiomyocyte and neural crest differentiation. Expression of mammalian Fermt3 is associated with hematopoietic lineages: the anterior ventral blood islands, vitelline veins, and early myeloid cells. In Xenopus embryos this expression, also include the notochord and cement gland. 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 568917006 275 PKLADYLKLFRPKKLMLKACKQYWFVFKDTSIAYFKNKELEQGEPIEKLNLRGCEIVPDVNVSGRKFGIKLLIPVADGMN 354
Cdd:cd01237    1 PELADYLKYFKPKKFTLKGYKRYWFVFKDTHLSYYKSKEESNGAPIQQINLKGCEVTPDVNVSQQKFCIKLLVPSPEGMS 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 568917006 355 EVYLRCDHEDQYARWMAACILASKGKTMADSSYQPEVISILSFLK 399
Cdd:cd01237   81 EVWLRCDNEDQYAKWMAACRLASKGKTMADSSYDSEVSSILAFLS 125

first ubiquitin-like (Ubl) domain located at the N-terminus of coronavirus SARS-CoV non-structural protein 3 (Nsp3) and related proteins; This ubiquitin-like (Ubl) domain (Ubl1) is found at the N-terminus of coronavirus Nsp3, a large multi-functional multi-domain protein which is an essential component of the replication/transcription complex (RTC). The functions of Ubl1 in CoVs are related to single-stranded RNA (ssRNA) binding and to interacting with the nucleocapsid (N) protein. SARS-CoV Ubl1 has been shown to bind ssRNA having AUA patterns, and since the 5'-UTR of the SARS-CoV genome has a number of AUA repeats, it may bind there. In mouse hepatitis virus (MHV), this Ubl1 domain binds the cognate N protein. Adjacent to Ubl1 is a Glu-rich acidic region (also referred to as hypervariable region, HVR); Ubl1 together with HVR has been called Nsp3a. Currently, the function of HVR in CoVs is unknown. This model corresponds to one of two Ubl domains in Nsp3; the other is located N-terminal to the papain-like protease (PLpro) and is not represented by this model.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568917006   1 MLRLRLPNAKTVRLRVSFSAVVFKAVADICKVLNIRRPEELSLLKPSsdyckkkkkkeknskepviedilnlessstssg 80
Cdd:cd17183    2 LLRLQLPNMKTVRLKVSFSAVVFKAVSDICKTLNIRRSEELSLLKPS--------------------------------- 48

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568917006  81 spvspglysktmtptydpingtpalstmtwfgdsplteqncsvlafsqpppspdvLADMFQPRSLVDKAKMNAGWLDSSR 160
Cdd:cd17183   49 -------------------------------------------------------LAKMYQPRTLLDKAKLNAGWLDSSR 73

                        170       180
                 ....*....|....*....|
gi 568917006 161 SLMEQSIQEDEQLQLRFKYY 180
Cdd:cd17183   74 SLMEQGIQEDDQLLLRFKYY 93

FERM central domain; This domain is the central structural domain of the FERM domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568917006  358 LRCDhEDQYARwMAACILASKGKTMADSSYQPEVISILSFLKMKNRNssplvasslenmdmnpeclvspccakKHKSKQL 437
Cdd:pfam00373  28 LPCS-EEEALL-LAALQLQAEFGDYQPSSHTSEYLSLESFLPKQLLR--------------------------KMKSKEL 79

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 568917006  438 AARILEAHHNVAQMPLVEAKLQFIQAWQSLPEFGLTYY 475
Cdd:pfam00373  80 EKRVLEAHKNLRGLSAEEAKLKYLQIAQSLPTYGVEFF 117

Fermitin family pleckstrin homology (PH) domain; Fermitin functions as a mediator of integrin inside-out signalling. The recruitment of Fermitin proteins and Talin to the membrane mediates the terminal event of integrin signalling, via interaction with integrin beta subunits. Fermatin has FERM domain interrupted with a pleckstrin homology (PH) domain. Fermitin family homologs (Fermt1, 2, and 3, also known as Kindlins) are each encoded by a different gene. In mammalian studies, Fermt1 is generally expressed in epithelial cells, Fermt2 is expressed inmuscle tissues, and Fermt3 is expressed in hematopoietic lineages. Specifically Fermt2 is expressed in smooth and striated muscle tissues in mice and in the somites (a trunk muscle precursor) and neural crest in Xenopus embryos. As such it has been proposed that Fermt2 plays a role in cardiomyocyte and neural crest differentiation. Expression of mammalian Fermt3 is associated with hematopoietic lineages: the anterior ventral blood islands, vitelline veins, and early myeloid cells. In Xenopus embryos this expression, also include the notochord and cement gland. 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 568917006 275 PKLADYLKLFRPKKLMLKACKQYWFVFKDTSIAYFKNKELEQGEPIEKLNLRGCEIVPDVNVSGRKFGIKLLIPVADGMN 354
Cdd:cd01237    1 PELADYLKYFKPKKFTLKGYKRYWFVFKDTHLSYYKSKEESNGAPIQQINLKGCEVTPDVNVSQQKFCIKLLVPSPEGMS 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 568917006 355 EVYLRCDHEDQYARWMAACILASKGKTMADSSYQPEVISILSFLK 399
Cdd:cd01237   81 EVWLRCDNEDQYAKWMAACRLASKGKTMADSSYDSEVSSILAFLS 125

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in kindlin-1 (KIND1); KIND1, also termed Kindlerin, or Kindler syndrome protein, or fermitin family homolog 1 (FERMT1), or Unc-112-related protein 1 (URP1), is an integrin-interacting protein that has been implicated in cell adhesion, proliferation, polarity, and motility. It is essential for maintaining the structure of cell-matrix adhesion, such as focal adhesions and podosomes. KIND1 is expressed primarily in epithelial cells. Loss or mutations of KIND1 gene may cause the Kindler syndrome (KS), an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. KIND1 forms a molecular complex with the key transforming growth factor (TGF)-beta/Smad3 signaling components including type I TGFbeta receptor (TbetaRI), Smad3 and Smad anchor for receptor activation (SARA) to control the activation of TGF-beta/Smad3 signaling pathway. KIND1 consists of an atypical FERM domain that is made up of F1, F2 and F3 domains, as well as an N-terminal region, which precedes the FERM domain and has been referred to as the F0 domain. This family corresponds to the F1 domain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568917006   1 MLRLRLPNAKTVRLRVSFSAVVFKAVADICKVLNIRRPEELSLLKPSsdyckkkkkkeknskepviedilnlessstssg 80
Cdd:cd17183    2 LLRLQLPNMKTVRLKVSFSAVVFKAVSDICKTLNIRRSEELSLLKPS--------------------------------- 48

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568917006  81 spvspglysktmtptydpingtpalstmtwfgdsplteqncsvlafsqpppspdvLADMFQPRSLVDKAKMNAGWLDSSR 160
Cdd:cd17183   49 -------------------------------------------------------LAKMYQPRTLLDKAKLNAGWLDSSR 73

                        170       180
                 ....*....|....*....|
gi 568917006 161 SLMEQSIQEDEQLQLRFKYY 180
Cdd:cd17183   74 SLMEQGIQEDDQLLLRFKYY 93

FERM central domain; This domain is the central structural domain of the FERM domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568917006  358 LRCDhEDQYARwMAACILASKGKTMADSSYQPEVISILSFLKMKNRNssplvasslenmdmnpeclvspccakKHKSKQL 437
Cdd:pfam00373  28 LPCS-EEEALL-LAALQLQAEFGDYQPSSHTSEYLSLESFLPKQLLR--------------------------KMKSKEL 79

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 568917006  438 AARILEAHHNVAQMPLVEAKLQFIQAWQSLPEFGLTYY 475
Cdd:pfam00373  80 EKRVLEAHKNLRGLSAEEAKLKYLQIAQSLPTYGVEFF 117

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 568917006   283 LFRPKKLMLKACKQYWFVFKDTSIAYFKNKELEQG-EPIEKLNLRGCEIVPDVN--VSGRKFGIKLLIPvadGMNEVYLR 359
Cdd:smart00233   7 LYKKSGGGKKSWKKRYFVLFNSTLLYYKSKKDKKSyKPKGSIDLSGCTVREAPDpdSSKKPHCFEIKTS---DRKTLLLQ 83

                           90
                   ....*....|....*....
gi 568917006   360 CDHEDQYARWMAACILASK 378
Cdd:smart00233  84 AESEEEREKWVEALRKAIA 102

Fermitin family pleckstrin homology (PH) domain; Fermitin functions as a mediator of integrin inside-out signalling. The recruitment of Fermitin proteins and Talin to the membrane mediates the terminal event of integrin signalling, via interaction with integrin beta subunits. Fermatin has FERM domain interrupted with a pleckstrin homology (PH) domain. Fermitin family homologs (Fermt1, 2, and 3, also known as Kindlins) are each encoded by a different gene. In mammalian studies, Fermt1 is generally expressed in epithelial cells, Fermt2 is expressed inmuscle tissues, and Fermt3 is expressed in hematopoietic lineages. Specifically Fermt2 is expressed in smooth and striated muscle tissues in mice and in the somites (a trunk muscle precursor) and neural crest in Xenopus embryos. As such it has been proposed that Fermt2 plays a role in cardiomyocyte and neural crest differentiation. Expression of mammalian Fermt3 is associated with hematopoietic lineages: the anterior ventral blood islands, vitelline veins, and early myeloid cells. In Xenopus embryos this expression, also include the notochord and cement gland. 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 568917006 275 PKLADYLKLFRPKKLMLKACKQYWFVFKDTSIAYFKNKELEQGEPIEKLNLRGCEIVPDVNVSGRKFGIKLLIPVADGMN 354
Cdd:cd01237    1 PELADYLKYFKPKKFTLKGYKRYWFVFKDTHLSYYKSKEESNGAPIQQINLKGCEVTPDVNVSQQKFCIKLLVPSPEGMS 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 568917006 355 EVYLRCDHEDQYARWMAACILASKGKTMADSSYQPEVISILSFLK 399
Cdd:cd01237   81 EVWLRCDNEDQYAKWMAACRLASKGKTMADSSYDSEVSSILAFLS 125

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in kindlin-1 (KIND1); KIND1, also termed Kindlerin, or Kindler syndrome protein, or fermitin family homolog 1 (FERMT1), or Unc-112-related protein 1 (URP1), is an integrin-interacting protein that has been implicated in cell adhesion, proliferation, polarity, and motility. It is essential for maintaining the structure of cell-matrix adhesion, such as focal adhesions and podosomes. KIND1 is expressed primarily in epithelial cells. Loss or mutations of KIND1 gene may cause the Kindler syndrome (KS), an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. KIND1 forms a molecular complex with the key transforming growth factor (TGF)-beta/Smad3 signaling components including type I TGFbeta receptor (TbetaRI), Smad3 and Smad anchor for receptor activation (SARA) to control the activation of TGF-beta/Smad3 signaling pathway. KIND1 consists of an atypical FERM domain that is made up of F1, F2 and F3 domains, as well as an N-terminal region, which precedes the FERM domain and has been referred to as the F0 domain. This family corresponds to the F1 domain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568917006   1 MLRLRLPNAKTVRLRVSFSAVVFKAVADICKVLNIRRPEELSLLKPSsdyckkkkkkeknskepviedilnlessstssg 80
Cdd:cd17183    2 LLRLQLPNMKTVRLKVSFSAVVFKAVSDICKTLNIRRSEELSLLKPS--------------------------------- 48

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568917006  81 spvspglysktmtptydpingtpalstmtwfgdsplteqncsvlafsqpppspdvLADMFQPRSLVDKAKMNAGWLDSSR 160
Cdd:cd17183   49 -------------------------------------------------------LAKMYQPRTLLDKAKLNAGWLDSSR 73

                        170       180
                 ....*....|....*....|
gi 568917006 161 SLMEQSIQEDEQLQLRFKYY 180
Cdd:cd17183   74 SLMEQGIQEDDQLLLRFKYY 93

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in kindlin-2 (KIND2); KIND2, also termed fermitin family homolog 2 (FERMT2), or mitogen-inducible gene 2 protein (MIG-2), or Pleckstrin homology (PH) domain-containing family C member 1, is an adaptor protein that is widely distributed and is particularly abundant in adherent cells. It binds to the integrin beta cytoplasmic tail to promote integrin activation. It promotes carcinogenesis through regulation of cell-cell and cell-extracellular matrix adhesion. KIND2 also plays an important role in cardiac development. KIND2 consists of an atypical FERM domain that is made up of F1, F2 and F3 domains, as well as an N-terminal region, which precedes the FERM domain and has been referred to as the F0 domain. This family corresponds to the F1 domain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568917006   1 MLRLRLPNAKTVRLRVSFSAVVFKAVADICKVLNIRRPEELSLLKPSSDyckkkkkkeknskepviedilnlessstssg 80
Cdd:cd17184    2 LLRLQLPNMKYVKVKVNFSDRVFKAVSDICKTFNIRHPEELSLLRKPRD------------------------------- 50

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568917006  81 spvspglysktmtptydpingtpalstmtwfgdsplteqncsvlafsqpPPSPDVLADMFQPRSLVDKAKMNAGWLDSSR 160
Cdd:cd17184   51 -------------------------------------------------PTKKKKLAKMYKPQSLLDKAKINQGWLDSSR 81

                        170       180
                 ....*....|....*....|
gi 568917006 161 SLMEQSIQEDEQLQLRFKYY 180
Cdd:cd17184   82 SLMEQDVKENEALLLRFKYY 101

Band 4.1 homologues; Also known as ezrin/radixin/moesin (ERM) protein domains. Present in myosins, ezrin, radixin, moesin, protein tyrosine phosphatases. Plasma membrane-binding domain. These proteins play structural and regulatory roles in the assembly and stabilization of specialized plasmamembrane domains. Some PDZ domain containing proteins bind one or more of this family. Now includes JAKs.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 568917006   155 WLDSSRSLMEQ-SIQEDEQLQLRFKYYTFFDLNPKYDAVRINQLYEQARWAVLLEEIDCTEEEMLIFAALQYHI 227
Cdd:smart00295  55 WLDPAKTLLDQdVKSEPLTLYFRVKFYPPDPNQLKEDPTRLNLLYLQVRNDILEGRLPCPEEEALLLAALALQA 128

FERM domain C-lobe; The FERM domain has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs), the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568917006 471 GLTYYLVRFKGSKK-DDILGVAYNRLIRIDAVTGIPVTTWRFANMKQWNVNW-EIRQVAIEF-DQNVSIAFTCLSADCKI 547
Cdd:cd00836    1 GVEFFPVKDKSKKGsPIILGVNPEGISVYDELTGQPLVLFPWPNIKKISFSGaKKFTIVVADeDKQSKLLFQTPSRQAKE 80

                         90
                 ....*....|.
gi 568917006 548 VHEYIGGYIFL 558
Cdd:cd00836   81 IWKLIVGYHRF 91

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 568917006   283 LFRPKKLMLKACKQYWFVFKDTSIAYFKNKELEQG-EPIEKLNLRGCEIVPDVN--VSGRKFGIKLLIPvadGMNEVYLR 359
Cdd:smart00233   7 LYKKSGGGKKSWKKRYFVLFNSTLLYYKSKKDKKSyKPKGSIDLSGCTVREAPDpdSSKKPHCFEIKTS---DRKTLLLQ 83

                           90
                   ....*....|....*....
gi 568917006   360 CDHEDQYARWMAACILASK 378
Cdd:smart00233  84 AESEEEREKWVEALRKAIA 102

Boi family Pleckstrin homology domain; Yeast Boi proteins Boi1 and Boi2 are functionally redundant and important for cell growth with Boi mutants displaying defects in bud formation and in the maintenance of cell polarity.They appear to be linked to Rho-type GTPase, Cdc42 and Rho3. Boi1 and Boi2 display two-hybrid interactions with the GTP-bound ("active") form of Cdc42, while Rho3 can suppress of the lethality caused by deletion of Boi1 and Boi2. These findings suggest that Boi1 and Boi2 are targets of Cdc42 that promote cell growth in a manner that is regulated by Rho3. Boi proteins contain a N-terminal SH3 domain, followed by a SAM (sterile alpha motif) domain, a proline-rich region, which mediates binding to the second SH3 domain of Bem1, and C-terminal PH domain. The PH domain is essential for its function in cell growth and is important for localization to the bud, while the SH3 domain is needed for localization to the neck. 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 568917006 295 KQYWFVFKDTSIAYFKNKELEQgepiEK--LNLRGCEIVPD--VNVSGRKFGIKLLIPVADGMNevYLRCDHEDQYARWM 370
Cdd:cd13316   17 KTRYFVLKGTRLYYLKSENDDK----EKglIDLTGHRVVPDdsNSPFRGSYGFKLVPPAVPKVH--YFAVDEKEELREWM 90

                 ....*..
gi 568917006 371 AACILAS 377
Cdd:cd13316   91 KALMKAT 97

Dual Adaptor for Phosphotyrosine and 3-Phosphoinositides Pleckstrin homology (PH) domain; DAPP1 (also known as PHISH/3' phosphoinositide-interacting SH2 domain-containing protein or Bam32) plays a role in B-cell activation and has potential roles in T-cell and mast cell function. DAPP1 promotes B cell receptor (BCR) induced activation of Rho GTPases Rac1 and Cdc42, which feed into mitogen-activated protein kinases (MAPK) activation pathways and affect cytoskeletal rearrangement. DAPP1can also regulate BCR-induced activation of extracellular signal-regulated kinase (ERK), and c-jun NH2-terminal kinase (JNK). DAPP1 contains an N-terminal SH2 domain and a C-terminal pleckstrin homology (PH) domain with a single tyrosine phosphorylation site located centrally. DAPP1 binds strongly to both PtdIns(3,4,5)P3 and PtdIns(3,4)P2. The PH domain is essential for plasma membrane recruitment of PI3K upon cell activation. 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
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 568917006 291 LKACKQYWFVFKDTSIAYFKNKELEqgEPIEKLNLRGCEIVPDVNVSGRKFGIKLLIP 348
Cdd:cd10573   16 VKNWKTRWFVLRRNELKYFKTRGDT--KPIRVLDLRECSSVQRDYSQGKVNCFCLVFP 71