Plant-like Phospholipase C (PLC) pleckstrin homology (PH) domain; PLC-gamma (PLCgamma) was the second class of PLC discovered. PLC-gamma consists of an N-terminal PH domain, a EF hand domain, a catalytic domain split into X and Y halves internal to which is a PH domain split by two SH2 domains and a single SH3 domain, and a C-terminal C2 domain. PLCs (EC 3.1.4.3) play a role in the initiation of cellular activation, proliferation, differentiation and apoptosis. They are central to inositol lipid signalling pathways, facilitating intracellular Ca2+ release and protein kinase C (PKC) activation. Specificaly, PLCs catalyze the cleavage of phosphatidylinositol-4,5-bisphosphate (PIP2) and result in the release of 1,2-diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). These products trigger the activation of protein kinase C (PKC) and the release of Ca2+ from intracellular stores. There are fourteen kinds of mammalian phospholipase C proteins which are are classified into six isotypes (beta, gamma, delta, epsilon, zeta, eta). This cd contains PLC members from fungi and plants. 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 334186523   17 RDIDQALVSLKKGTQLLKYSRKGRPKFRSFRLSPDETTLFWLS--HGEEKGLKLATVSRILPGQRTAVFRRYLRPEKDYL 94
Cdd:cd13365     1 RDVIEAITQLKIGSYLLKYGRRGKPHFRYFWLSPDELTLYWSSpkKGSEKRVRLSSVSRIIPGQRTVVFKRPPPPGLEEH 80

                          90       100       110
                  ....*....|....*....|....*....|....
gi 334186523   95 SFSLIYHNGDRSLDLICKDKAETEVWFAGLKSLI 128
Cdd:cd13365    81 SFSIIYADGERSLDLTCKDRQEFDTWFTGLRYLL 114

Transcription factor regulating root and shoot growth via Pin3; The BREVIS RADIX (BRX) domain was characterized as being a transcription factor in plants regulating the extent of cell proliferation and elongation in the growth zone of the root. BRX is rate limiting for auxin-responsive gene-expression by mediating cross-talk with the brassino-steroid pathway. BRX has a ubiquitous, although quantitatively variable role in modulating the growth rate in both the root and the shoot. The family features a short region of alpha-helix, approximately 60 residues in length, which is found repeated up to three times. BRX is expressed in the vasculature and is rate-limiting for transcriptional auxin action.

                           10        20        30
                   ....*....|....*....|....*....|.
gi 334186523   964 KELIEQFEPGVYVTYVLHKNGGKIFRRVRFS 994
Cdd:pfam08381    2 REWVEQDEPGVYITLVILPDGTKELKRVRFS 32

Plant-like Phospholipase C (PLC) pleckstrin homology (PH) domain; PLC-gamma (PLCgamma) was the second class of PLC discovered. PLC-gamma consists of an N-terminal PH domain, a EF hand domain, a catalytic domain split into X and Y halves internal to which is a PH domain split by two SH2 domains and a single SH3 domain, and a C-terminal C2 domain. PLCs (EC 3.1.4.3) play a role in the initiation of cellular activation, proliferation, differentiation and apoptosis. They are central to inositol lipid signalling pathways, facilitating intracellular Ca2+ release and protein kinase C (PKC) activation. Specificaly, PLCs catalyze the cleavage of phosphatidylinositol-4,5-bisphosphate (PIP2) and result in the release of 1,2-diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). These products trigger the activation of protein kinase C (PKC) and the release of Ca2+ from intracellular stores. There are fourteen kinds of mammalian phospholipase C proteins which are are classified into six isotypes (beta, gamma, delta, epsilon, zeta, eta). This cd contains PLC members from fungi and plants. 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 334186523   17 RDIDQALVSLKKGTQLLKYSRKGRPKFRSFRLSPDETTLFWLS--HGEEKGLKLATVSRILPGQRTAVFRRYLRPEKDYL 94
Cdd:cd13365     1 RDVIEAITQLKIGSYLLKYGRRGKPHFRYFWLSPDELTLYWSSpkKGSEKRVRLSSVSRIIPGQRTVVFKRPPPPGLEEH 80

                          90       100       110
                  ....*....|....*....|....*....|....
gi 334186523   95 SFSLIYHNGDRSLDLICKDKAETEVWFAGLKSLI 128
Cdd:cd13365    81 SFSIIYADGERSLDLTCKDRQEFDTWFTGLRYLL 114

FYVE zinc finger; The FYVE zinc finger is named after four proteins that it has been found in: Fab1, YOTB/ZK632.12, Vac1, and EEA1. The FYVE finger has been shown to bind two Zn++ ions. The FYVE finger has eight potential zinc coordinating cysteine positions. Many members of this family also include two histidines in a motif R+HHC+XCG, where + represents a charged residue and X any residue. We have included members which do not conserve these histidine residues but are clearly related.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 334186523   614 KWVSGADQSVCSGCRQAFGFTRKRHNCYNCGLVHCHACSSKKALKAALAPTpGKPHRVCDACYTKL 679
Cdd:pfam01363    2 VWVPDSSATVCMICSKPFTFFRRRHHCRNCGRVFCSACSSKKISLLPELGS-NKPVRVCDACYDTL 66

Regulator of chromosome condensation (RCC1) repeat;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*
gi 334186523   563 EVFTWGKGSNGRLGHGDKDDRKTPTLVEALRERHVKSISCGSNFT 607
Cdd:pfam00415    3 RVYTWGRNDYGQLGLGTTENVLVPQKVEGLSGNKVVQVACGGDHT 47

Transcription factor BRX N-terminal domain; The BREVIS RADIX (BRX) domain was characterized as being a transcription factor in plants regulating the extent of cell proliferation and elongation in the growth zone of the root. BRX is rate limiting for auxin-responsive gene-expression by mediating cross-talk with the brassino-steroid pathway. BRX has a ubiquitous, although quantitatively variable role in modulating the growth rate in both the root and the shoot. This family features a short region, also alpha-helical, N-terminal to the repeated alpha-helices of family BRX, pfam08381. BRX is expressed in the vasculature and is rate-limiting for transcriptional auxin action.

                           10        20        30
                   ....*....|....*....|....*....|....*..
gi 334186523   853 KHSSKHKAATEVMKSVAEHLRELKEKLPPEVSRCEAF 889
Cdd:pfam13713    1 EESSKTKAAKEVIKSLTAQLKDMAEKLPGAYRDCKPC 37

Alpha-tubulin suppressor ATS1 and related RCC1 domain-containing proteins [Cell cycle control, cell division, chromosome partitioning, Cytoskeleton];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 334186523  230 GDVYVWGEVWS----DGISPDGvvnSTTVKIDVLipkpleSNVVldvhQIACGVRHIALVTRQGEVFTWEEEAGGRLGHG 305
Cdd:COG5184    17 GTVWCWGDNSYgqlgDGTTTDR---STPVRVPGL------SNVV----AVAAGGDHTCALKADGTVWCWGNNSYGQLGDG 83

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 334186523  306 IQVDVCRPKLVEflALTNIDFVACGEYHTCAVSTSGDLFTWGDGIHnvGLLGHGSDLSHWIPKRVSGPVEGlqVLSVACG 385
Cdd:COG5184    84 TTTDRTTPVKVP--GLTGVVAVAAGYYHSCALKSDGTVWCWGDNSS--GQLGDGTTTNRLTPVQVDAGLSG--VVAIAAG 157

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 334186523  386 TWHSALATANGKLFTFGDGAFGVLGHGDRESVSYPKEVKMLSGLKtlKVACGVWHTVAIvevmnqtgtsTSSRKLFTWGD 465
Cdd:COG5184   158 GYHTCALKSDGTVWCWGANSYGQLGDGTTTDRPTPVQVGGLSGVV--AVAAGGDHSCAL----------KSDGTVWCWGS 225

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 334186523  466 GDKNRLGHGNKETYLLPTCVSSLidYNFNQIACGHTFTVALTTSGHVFTMGGTSHGQLGSSNSDGKL-PCLVQDrlvGEF 544
Cdd:COG5184   226 NSSGQLGDGTTTDRATPVQVAGL--TGVVAIAAGGSHTCALKSDGTVWCWGDNSYGQLGDGTTTDRStPVKVPG---LSG 300

                         330       340       350       360
                  ....*....|....*....|....*....|....*....|...
gi 334186523  545 VEEISCGDHHVAVLTSRSEVFTWGKGSNGRLGHGDKDDRKTPT 587
Cdd:COG5184   301 VVAVAAGSSHTCALLTDGTVWCWGDNAYGQLGDGTTTDRSTPV 343

Phospholipase C and Engulfment and cell motility protein 1 pleckstrin homology domain; The C-terminal region of ELMO1, the PH domain and Pro-rich sequences, binds the SH3-containing region of DOCK2 forming a intermolecular five-helix bundle allowing for DOCK mediated Rac1 activation. ELMO1, a mammalian homolog of C. elegans CED-12, contains an N-terminal RhoG-binding region, a ELMO domain, a PH domain, and a C-terminal sequence with three PxxP motifs. Specificaly, PLCs catalyze the cleavage of phosphatidylinositol-4,5-bisphosphate (PIP2) and result in the release of 1,2-diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). These products trigger the activation of protein kinase C (PKC) and the release of Ca2+ from intracellular stores. There are fourteen kinds of mammalian phospholipase C which are are classified into six isotypes (beta, gamma, delta, epsilon, zeta, eta). All PLCs, except for PLCzeta, have a PH domain which is for most part N-terminally located, though lipid binding specificity is not conserved between them. In addition PLC gamma contains a split PH domain within its catalytic domain that is separated by 2 SH2 domains and a single SH3 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 334186523   26 LKKGTQLLKYSRKGRPKFRSFRLSPDETTLFWLSHGEEKGLK---LATVSRILPGQRTAVFRRYLRP--EKDYLSFSLIY 100
Cdd:cd01248     1 LQQGTLLLKYREGSKPKERTFYLDPDGTRITWESSKKKSEKKsidISDIKEIRPGKDTDGFKRKKKSnkPKEERCFSIIY 80

                          90       100
                  ....*....|....*....|....*...
gi 334186523  101 HNGDRSLDLICKDKAETEVWFAGLKSLI 128
Cdd:cd01248    81 GSNNKTLDLVAPSEDEANLWVEGLRALL 108

FYVE zinc finger; The FYVE zinc finger is named after four proteins that it has been found in: Fab1, YOTB/ZK632.12, Vac1, and EEA1. The FYVE finger has been shown to bind two Zn++ ions. The FYVE finger has eight potential zinc coordinating cysteine positions. Many members of this family also include two histidines in a motif R+HHC+XCG, where + represents a charged residue and X any residue. We have included members which do not conserve these histidine residues but are clearly related.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 334186523   614 KWVSGADQSVCSGCRQAFGFTRKRHNCYNCGLVHCHACSSKKALKAALAPTpGKPHRVCDACYTKL 679
Cdd:pfam01363    2 VWVPDSSATVCMICSKPFTFFRRRHHCRNCGRVFCSACSSKKISLLPELGS-NKPVRVCDACYDTL 66

FYVE domain found in RUN and FYVE domain-containing protein RUFY1, RUFY2 and similar proteins; This family includes RUN and FYVE domain-containing protein RUFY1 and RUFY2. RUFY1, also termed FYVE-finger protein EIP1, or La-binding protein 1, or Rab4-interacting protein (Rabip4), or Zinc finger FYVE domain-containing protein 12 (ZFY12), a human homologue of mouse Rabip4, an effector of Rab4 GTPase that regulates recycling of endocytosed cargo. RUFY1 is an endosomal protein that functions as a dual effector of Rab4 and Rab14 and is involved in efficient recycling of transferrin (Tfn). It is a downstream effector of Etk, a downstream tyrosine kinase of PI3-kinase that is involved in regulation of vesicle trafficking. RUFY2, also termed Rab4-interacting protein related, is a novel embryonic factor that is present in the nucleus at early stages of embryonic development. It may have both endosomal functions in the cytoplasm and nuclear functions. Both RUFY1 and RUFY2 contain an N-terminal RUN domain and a C-terminal FYVE domain with two coiled-coil domains in-between.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 334186523  615 WVSGADQSVCSGCRQAFGFTRKRHNCYNCGLVHCHACSSKkalKAALaPTPGKPHRVCDACY 676
Cdd:cd15721     1 WADDKEVTHCQQCEKEFSLSRRKHHCRNCGGIFCNSCSDN---TMPL-PSSAKPVRVCDTCY 58

Regulator of chromosome condensation (RCC1) repeat;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*
gi 334186523   563 EVFTWGKGSNGRLGHGDKDDRKTPTLVEALRERHVKSISCGSNFT 607
Cdd:pfam00415    3 RVYTWGRNDYGQLGLGTTENVLVPQKVEGLSGNKVVQVACGGDHT 47

Regulator of chromosome condensation (RCC1) repeat;

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|
gi 334186523   395 NGKLFTFGDGAFGVLGHGDRESVSYPKEVKMLSGLKTLKVACGVWHTVAI 444
Cdd:pfam00415    1 DGRVYTWGRNDYGQLGLGTTENVLVPQKVEGLSGNKVVQVACGGDHTVAL 50

FYVE domain found in hepatocyte growth factor (HGF)-regulated tyrosine kinase substrate (Hrs) and similar proteins; Hrs, also termed protein pp110, is a tyrosine phosphorylated protein that plays an important role in the signaling pathway of HGF. It is localized to early endosomes and an essential component of the endosomal sorting and trafficking machinery. Hrs interacts with hypertonia-associated protein Trak1, a novel regulator of endosome-to-lysosome trafficking. It can also forms an Hrs/actinin-4/BERP/myosin V protein complex that is required for efficient transferrin receptor (TfR) recycling but not for epidermal growth factor receptor (EGFR) degradation. Moreover, Hrs, together with STAM proteins, STAM1 and STAM2, and EPs15, forms a multivalent ubiquitin-binding complex that sorts ubiquitinated proteins into the multivesicular body pathway, and plays a regulatory role in endocytosis/exocytosis. Furthermore, Hrs functions as an interactor of the neurofibromatosis 2 tumor suppressor protein schwannomin/merlin. It is also involved in the inhibition of citron kinase-mediated HIV-1 budding. Hrs contains a single ubiquitin-interacting motif (UIM) that is crucial for its function in receptor sorting, and a FYVE domain that harbors double Zn2+ binding sites.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 334186523  619 ADQSVCSGCRQAFGFTRKRHNCYNCGLVHCHACSSKKalkaALAPTPG--KPHRVCDACYTKL 679
Cdd:cd15720     3 KDGDECHRCRVQFGVFQRKHHCRACGQVFCGKCSSKS----STIPKFGieKEVRVCDPCYEKL 61

FYVE domain found in RUN and FYVE domain-containing protein 1 (RUFY1) and similar proteins; RUFY1, also termed FYVE-finger protein EIP1, or La-binding protein 1, or Rab4-interacting protein (Rabip4), or Zinc finger FYVE domain-containing protein 12 (ZFY12), a human homologue of mouse Rabip4, an effector of Rab4 GTPase that regulates recycling of endocytosed cargo. RUFY1 is an endosomal protein that functions as a dual effector of Rab4 and Rab14 and is involved in efficient recycling of transferrin (Tfn). It is a downstream effector of Etk, a downstream tyrosine kinase of PI3-kinase that is involved in regulation of vesicle trafficking. RUFY1 contains an N-terminal RUN domain and a C-terminal FYVE domain with two coiled-coil domains in-between.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 334186523  613 HKWVSGADQSVCSGCRQAFGFTRKRHNCYNCGLVHCHACSSKkalKAALAPTPgKPHRVCDACYTKL 679
Cdd:cd15758     4 HAWLKDDEATHCKQCEKEFSISRRKHHCRNCGHIFCNTCSSN---ELALPSYP-KPVRVCDSCHTLL 66

FYVE domain found in endofin and similar proteins; Endofin, also termed zinc finger FYVE domain-containing protein 16 (ZFY16), or endosome-associated FYVE domain protein, is a FYVE domain-containing protein that is localized to EEA1-containing endosomes. It is regulated by phosphoinositol lipid and engaged in endosome-mediated receptor modulation. Endofin is involved in Bone morphogenetic protein (BMP) signaling through interacting with Smad1 preferentially and enhancing Smad1 phosphorylation and nuclear localization upon BMP stimulation. It also functions as a scaffold protein that brings Smad4 to the proximity of the receptor complex in Transforming growth factor (TGF)-beta signaling. Moreover, endofin is a novel tyrosine phosphorylation target downstream of epidermal growth factor receptor (EGFR) in EGF-signaling. In addition, endofin plays a role in endosomal trafficking by recruiting cytosolic TOM1, an important molecule for membrane recruitment of clathrin, onto endosomal membranes.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 334186523  615 WVSGADQSVCSGCRQAFGFTRKRHNCYNCGLVHCHACSSkkaLKAALAPTPGKPHRVCDACYTKL 679
Cdd:cd15729     7 WVPDSEAPNCMQCEVKFTFTKRRHHCRACGKVLCSACCS---LKARLEYLDNKEARVCVPCYQTL 68

FYVE domain found in protein containing both PH and FYVE domains 2 (phafin-2) and similar proteins; Phafin-2, also termed endoplasmic reticulum-associated apoptosis-involved protein containing PH and FYVE domains (EAPF), or pleckstrin homology domain-containing family F member 2 (PKHF2), or PH domain-containing family F member 2, or PH and FYVE domain-containing protein 2, or zinc finger FYVE domain-containing protein 18, is a ubiquitously expressed endoplasmic reticulum-associated protein that facilitates tumor necrosis factor alpha (TNF-alpha)-triggered cellular apoptosis through endoplasmic reticulum (ER)-mitochondrial apoptotic pathway. It is an endosomal phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) effector, as well as an interactor of the endosomal-tethering protein EEA1. It regulates endosome fusion upstream of Rab5. Phafin-2 also functions as a novel regulator of endocytic epidermal growth factor receptor (EGFR) degradation through a role in endosomal fusion.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 334186523  615 WVSGADQSVCSGCRQA-FGFTRKRHNCYNCGLVHCHACSSKKALkaaLAPTPGKPHRVCDACYTKL 679
Cdd:cd15755     2 WVPDSEATVCMRCQKAkFTPVNRRHHCRKCGFVVCGPCSEKKFL---LPSQSSKPVRVCDFCYDLL 64

FYVE domain found in protein containing both PH and FYVE domains 1 (phafin-1) and similar proteins; Phafin-1, also termed lysosome-associated apoptosis-inducing protein containing PH (pleckstrin homology) and FYVE domains (LAPF), or pleckstrin homology domain-containing family F member 1 (PKHF1), or PH domain-containing family F member 1, or apoptosis-inducing protein, or PH and FYVE domain-containing protein 1, or zinc finger FYVE domain-containing protein 15, is a representative of a novel family of PH and FYVE domain-containing proteins called phafins. It is a ubiquitously expressed pro-apoptotic protein via translocating to lysosomes, facilitating apoptosis induction through a lysosomal-mitochondrial apoptotic pathway.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 334186523  615 WVSGADQSVCSGCRQA-FGFTRKRHNCYNCGLVHCHACSSKKALKAALAPtpgKPHRVCDACYTKL 679
Cdd:cd15754     2 WIPDKATDICMRCTQTnFSLLTRRHHCRKCGFVVCHECSRQRFLIPRLSP---KPVRVCSLCYRKL 64

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        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 334186523  615 WVSGADQSVCSGCRQAFGFTRKRHNCYNCGLVHCHACSSKKalkaalAPTPGK----PHRVCDACY 676
Cdd:cd15733     1 WVPDHAASHCFGCDCEFWLAKRKHHCRNCGNVFCADCSNYK------LPIPDEqlydPVRVCNSCY 60

Pleckstrin homology domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 334186523    21 QALVSLKKGTQLLKYSRKGRP-KFRSFRLSPDETTLFW------------LSHGEEKgLKLATVSRILPGQRTAVFRR-- 85
Cdd:pfam16457    4 QRLNCLLEGAWFPKVRGRRRKkKYRFCRLSPNRKVLHYgdfeekptvdpsLESLPEK-IDLSDIKEVVTGKECPHVREsg 82

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*
gi 334186523    86 -YLRPEKDYLSFSLIY-HNGDRSLDLICKDKAETEVWFAGLKSLI 128
Cdd:pfam16457   83 kKSKKTSSTLAFSLIYgADEYELLDFVAPSESVAAIWLDGLNMLL 127

FYVE-related domain found in RUN and FYVE domain-containing protein 3 (RUFY3) and similar proteins; RUFY3, also termed Rap2-interacting protein x (RIPx or RPIPx), or single axon-regulated protein (singar), is an N-terminal RUN domain and a C-terminal FYVE domain containing protein predominantly expressed in the brain. It suppresses formation of surplus axons for neuronal polarity. Unlike other RUFY proteins, RUFY3 can associate with the GTP-bound active form of Rab5. Moreover, the FYVE domain of RUFY3 resembles the FYVE-related domain as it lacks the WxxD motif (x for any residue).

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 334186523  624 CSGCRQAFGF-TRKRHNCYNCGLVHCHACSSKKALkaaLAPTPGKPHRVCDACY 676
Cdd:cd15744     2 CSLCQEDFASlALPKHNCYNCGGTFCDACSSNELP---LPSSIYEPARVCDVCY 52

FYVE domain found in FYVE domain-containing protein 26 (ZFY26 or ZFYVE26); ZFY26, also termed FYVE domain-containing centrosomal protein (FYVE-CENT), or spastizin, is a phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) binding protein that localizes to the centrosome and midbody. ZFY26 and its interacting partners TTC19 and KIF13A are required for cytokinesis. It also interacts with Beclin 1, a subunit of class III phosphatidylinositol 3-kinase complex, and may have potential implications for carcinogenesis. In addition, it has been considered as the causal agent of a rare form of hereditary spastic paraplegia. ZFY26 contains a FYVE domain that is important for targeting of FYVE-CENT to the midbody.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 334186523  615 WVSGADQSVCSGC-RQAFGFTRKRHNCYNCGLVHCHACSSKKALKAALAptpGKPHRVCDACY 676
Cdd:cd15724     1 WVPDEAVSVCMVCqVERFSMFNRRHHCRRCGRVVCSSCSTKKMLVEGYR---ENPVRVCDQCY 60

FYVE domain found in FYVE, RhoGEF and PH domain-containing protein 6 (FGD6) and similar proteins; FGD6, also termed zinc finger FYVE domain-containing protein 24 is a putative Cdc42-specific guanine nucleotide exchange factor (GEF) whose biological function remains unclear. It is a homologue of FGD1 and contains a DBL homology (DH) domain and pleckstrin homology (PH) domain in the middle region, a FYVE domain, and another PH domain in the C-terminus, but lacks the N-terminal proline-rich domain (PRD) found in FGD1. Moreover, the FYVE domain of FGD6 is a canonical FYVE domain, which has been found in many proteins involved in membrane trafficking and phosphoinositide metabolism, and has been defined by three signature sequences: an N-terminal WxxD motif (x for any residue), the central basic R(R/K)HHCR patch, and a C-terminal RVC motif, which form a compact phosphatidylinositol 3-phosphate (PtdIns3P or PI3P)-binding site.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 334186523  615 WVSGADQSVCSGCRQAFGFTRKRHNCYNCGLVHCHACSSKkalKAALAPTPGKPHRVCDACY 676
Cdd:cd15743     3 WIPDSRVTMCMICTSEFTVTWRRHHCRACGKVVCGSCSSN---KAPLEYLKNKSARVCDECF 61

FYVE domain found in myotubularin-related protein 3 (MTMR3) and similar proteins; MTMR3, also termed Myotubularin-related phosphatase 3, or FYVE domain-containing dual specificity protein phosphatase 1 (FYVE-DSP1), or zinc finger FYVE domain-containing protein 10, is a ubiquitously expressed phosphoinositide 3-phosphatase specific for phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) and phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) and PIKfyve, which produces PtdIns(3,5)P2 from PtdIns3P. It regulates cell migration through modulating phosphatidylinositol 5-phosphate (PtdIns5P) levels. MTMR3 contains an N-terminal PH-GRAM (PH-G) domain, a MTM phosphatase domain, a coiled-coil region, and a C-terminal FYVE domain. Unlike conventional FYVE domains, the FYVE domain of MTMR3 neither confers endosomal localization nor binds to PtdIns3P. It is also not required for the enzyme activity of MTMR3. In contrast, the PH-G domain binds phosphoinositides.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 334186523  614 KWVSGADQSVCSGCRQAFGFTRKRHNCYNCGLVHCHACSSKKalkaalAPTPG----KPHRVCDACY 676
Cdd:cd15732     1 RWVPDHLAASCYGCEREFWLASRKHHCRNCGNVFCGSCCNQK------LPVPSqqlfEPSRVCKSCF 61

FYVE-related domain found in protrudin and similar proteins; Protrudin, also termed zinc finger FYVE domain-containing protein 27 (ZFY27 or ZFYVE27), is a FYVE domain-containing protein involved in transport of neuronal cargoes and implicated in the onset of hereditary spastic paraplegia (HSP). It is involved in neurite outgrowth through binding to spastin. Moreover, it functions as a key regulator of the Rab11-dependent membrane trafficking during neurite extension. It serves as an adaptor molecule that links its associated proteins, such as Rab11-GDP, VAP-A and -B, Surf4, and RTN3, to KIF5, a motor protein that mediates anterograde vesicular transport in neurons, and thus plays a key role in the maintenance of neuronal function. The FYVE domain of protrudin resembles a FYVE-related domain that is structurally similar to the canonical FYVE domains but lacks the 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. In addition, unlike canonical FYVE domains that is located to early endosomes and specifically binds to phosphatidylinositol 3-phosphate (PtdIns3P or PI3P), the FYVE domain of protrudin is located to plasma membrane and preferentially binds phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2), and phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3). In addition to FYVE-related domain, protrudin also contains a Rab11-binding domain (RBD11), two hydrophobic domains, HP-1 and HP-2, an FFAT motif, and a coiled-coil domain.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 334186523  624 CSGCRQAFG-FTRKRHNCYNCGLVHCHACSSKKALKAALAPTPGKPHR----VCDACYTKL 679
Cdd:cd15723     2 CTGCGASFSvLLKKRRSCNNCGNAFCSRCCSKKVPRSVMGATAPAAQRetvfVCSGCNDKL 62

Regulator of chromosome condensation (RCC1) repeat;

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                   ....*....|....*....|....*....|....*....|....*....
gi 334186523   289 GEVFTWEEEAGGRLGHGIQVDVCRPKLVEFLALTNIDFVACGEYHTCAV 337
Cdd:pfam00415    2 GRVYTWGRNDYGQLGLGTTENVLVPQKVEGLSGNKVVQVACGGDHTVAL 50

Phospholipase C-eta (PLC-eta) pleckstrin homology (PH) domain; PLC-eta (PLCeta) consists of two enzymes, PLCeta1 and PLCeta2. They hydrolyze phosphatidylinositol 4,5-bisphosphate, are more sensitive to Ca2+ than other PLC isozymes, and involved in PKC activation in the brain and neuroendocrine systems. PLC-eta consists of an N-terminal PH domain, a EF hand domain, a catalytic domain split into X and Y halves by a variable linker, a C2 domain, and a C-terminal PDZ domain. PLCs (EC 3.1.4.3) play a role in the initiation of cellular activation, proliferation, differentiation and apoptosis. They are central to inositol lipid signalling pathways, facilitating intracellular Ca2+ release and protein kinase C (PKC) activation. Specificaly, PLCs catalyze the cleavage of phosphatidylinositol-4,5-bisphosphate (PIP2) and result in the release of 1,2-diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). These products trigger the activation of protein kinase C (PKC) and the release of Ca2+ from intracellular stores. There are fourteen kinds of mammalian phospholipase C proteins which are are classified into six isotypes (beta, gamma, delta, epsilon, zeta, eta). 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.involved in targeting proteins to the plasma membrane, but only a few (less than 10%) display strong specificity in binding inositol phosphates. 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 kinases, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, cytoskeletal associated molecules, and in lipid associated enzymes.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 334186523   26 LKKGTQLLKYSRKGRPKFRSFRLSPDETTLFWL--SHGEEKG-LKLATVSRILPGQRTAVFRRYLRPE--KDYLSFSLIY 100
Cdd:cd13364     1 MQEGSELVKVRSNSRQYRRFFYLDEDKSSIRWKpsKKKSEKAkIPISSIREVREGKTTDIFRSCDISGdfPEECCFSIIY 80

                          90       100
                  ....*....|....*....|....*...
gi 334186523  101 HNGDRSLDLICKDKAETEVWFAGLKSLI 128
Cdd:cd13364    81 GEEYETLDLVASSPDEANIWITGLRYLM 108

FYVE-related domain found in RUN and FYVE domain-containing protein 4 (RUFY4) and similar proteins; RUFY4 belongs to the FUFY protein family which is characterized by the presence of an N-terminal RUN domain and a C-terminal FYVE domain. The FYVE domain of RUFY4 resembles the FYVE-related domain as it lacks the WxxD motif (x for any residue). The biological function of RUFY4 still remains unclear.

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                  ....*....|....*....|....*....|....*....|....*....|...
gi 334186523  624 CSGCRQAFGFTRKRHNCYNCGLVHCHACSSKKALKAalAPTPGKPHRVCDACY 676
Cdd:cd15745     2 CAICAKAFSLFRRKYVCRLCGGVVCHSCSSEDLVLS--VPDTCIYLRVCKTCY 52

FYVE-like domain found in FYVE, RhoGEF and PH domain-containing protein 5 (FGD5) and similar proteins; FGD5, also termed zinc finger FYVE domain-containing protein 23, is an endothelial cell (EC)-specific guanine nucleotide exchange factor (GEF) that regulates endothelial adhesion, survival, and angiogenesis by modulating phosphatidylinositol 3-kinase signaling. It functions as a novel genetic regulator of vascular pruning by activation of endothelial cell-targeted apoptosis. FGD5 is a homologue of FGD1 and contains a DBL homology (DH) domain, a pleckstrin homology (PH) domain, a FYVE domain, and another PH domain in the C-terminus, but lacks the N-terminal proline-rich domain (PRD) found in FGD1. The FYVE domain of FGD5 resembles a FYVE-like domain that is different from the canonical FYVE domains, since it lacks one of the three conserved signature motifs (the WxxD motif) that are involved in phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) binding and exhibits altered lipid binding specificities.

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                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 334186523  623 VCSGCRQAFGFTRKRHNCYNCGLVHCHACSSKkalKAALAPTPGKPHRVCDACYTKLK 680
Cdd:cd15742    11 MCMNCGSDFTLTLRRHHCHACGKIVCRNCSRN---KYPLKYLKDRPAKVCDGCFAELR 65

FYVE domain 2 found in yeast protein VAC1 (Vac1p) and similar proteins; Vac1p, also termed vacuolar segregation protein Pep7p, or carboxypeptidase Y-deficient protein 7, or vacuolar protein sorting-associated protein 19 (Vps19p), or vacuolar protein-targeting protein 19, is a phosphatidylinositol 3-phosphate (PtdIns3P or PI3P)-binding protein that interacts with a Rab GTPase, GTP-bound form of Vps21p, and a Sec1p homologue, Vps45p, to facilitate Vps45p-dependent vesicle-mediated vacuolar protein sorting. It also acts as a novel regulator of vesicle docking and/or fusion at the endosome and functions in vesicle-mediated transport of Golgi precursor carboxypeptidase Y (CPY), protease A (PrA), protease B (PrB), but not alkaline phosphatase (ALP) from the trans-Golgi network-like compartment (TGN) to the endosome. Vac1p contains an N-terminal classical TFIIIA-like zinc finger, two putative zinc-binding FYVE fingers, and a C-terminal coiled coil region. The family corresponds to the second FYVE domain that is responsible for the ability of Pep7p to efficiently interact with Vac1p and Vps45p.

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                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 334186523  614 KWVSGADQSVCSGCRQAFGFTRKRHNCYNCGLVHCH----ACSSKKALKAALAPTPGKP 668
Cdd:cd15737     1 PWEDDSSVTHCPICLRSFGLLLRKHHCRLCGKVVCDdrrtKCSTEVPLDLLSSALPDLP 59

FYVE-related domain found in uncharacterized myotubularin-related proteins mainly from eumetazoa; This family includes a group of uncharacterized myotubularin-related proteins mainly found in eumetazoa. Although their biological functions remain unclear, they share similar domain architecture that consists of an N-terminal pleckstrin homology (PH) domain, a highly conserved region related to myotubularin proteins, a C-terminal FYVE domain. The model corresponds to the FYVE domain, which resembles the FYVE-related domain as it has an altered sequence in the basic ligand binding patch.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 334186523  613 HKWVSGADQSVCSgCRQAFGFTRKRHNCYNCGLVHCHACSSKKAlkAALAPTPGKPHRVCDACY 676
Cdd:cd15738     1 LDWKSFRNVTECS-CSTPFDHFSKKHHCWRCGNVFCTRCIDKQR--ALPGHLSQRPVPVCRACY 61

FYVE domain found in Saccharomyces cerevisiae vacuolar protein sorting-associated protein 27 (scVps27p) and FYVE-related domain 1 found in yeast protein VAC1 (Vac1p) and similar proteins; The family includes Saccharomyces cerevisiae vacuolar protein sorting-associated protein 27 (scVps27p) and protein VAC1 (Vac1p). scVps27p, also termed Golgi retention defective protein 11, is the putative yeast counterpart of the mammalian protein Hrs and is involved in endosome maturation. It is a mono-ubiquitin-binding protein that interacts with ubiquitinated cargoes, such as Hse1p, and is required for protein sorting into the multivesicular body. Vps27p forms a complex with Hse1p. The complex binds ubiquitin and mediates endosomal protein sorting. At the endosome, Vps27p and a trimeric protein complex, ESCRT-1, bind ubiquitin and are important for multivesicular body (MVB) sorting. Vps27p contains an N-terminal VHS (Vps27/Hrs/STAM) domain, a FYVE domain that binds PtdIns3P, followed by two ubiquitin-interacting motifs (UIMs), and a C-terminal clathrin-binding motif. Vac1p, also termed vacuolar segregation protein Pep7p, or carboxypeptidase Y-deficient protein 7, or vacuolar protein sorting-associated protein 19 (Vps19p), or vacuolar protein-targeting protein 19, is a phosphatidylinositol 3-phosphate (PtdIns3P or PI3P)-binding protein that interacts with a Rab GTPase, GTP-bound form of Vps21p, and a Sec1p homologue, Vps45p, to facilitate Vps45p-dependent vesicle-mediated vacuolar protein sorting. It also acts as a novel regulator of vesicle docking and/or fusion at the endosome and functions in vesicle-mediated transport of Golgi precursor carboxypeptidase Y (CPY), protease A (PrA), protease B (PrB), but not alkaline phosphatase (ALP) from the trans-Golgi network-like compartment (TGN) to the endosome. Vac1p contains an N-terminal classical TFIIIA-like zinc finger, two putative zinc-binding FYVE fingers, and a C-terminal coiled coil region. The FYVE domain in both Vps27p and Vac1p harbors a zinc-binding site composed of seven Cysteines and one Histidine, which is different from that of other FYVE domain containing proteins.

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                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 334186523  623 VCSGCRQAFGFTRKRHNCYNCGLVHC--HACSSKKALKAALAPTPGKPHRVCDACY 676
Cdd:cd15736     1 CCHTCSRTFNLNIRAHHCRKCGKLFCrrHLPNMIPLNLSAYDPRNGKWYRCCHSCF 56

FYVE-like domain found in caspase-associated ring proteins, CARP1 and CARP2; CARP1 and CARP2 are a novel group of caspase regulators by the presence of a FYVE-type zinc finger domain. 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 (x for any residue) motif that is conserved only in phosphoinositide binding FYVE domains. Thus they constitute a family of unique FYVE-type domains called FYVE-like domains.