protein kinase C conserved region 1 (C1 domain) found in RAS guanyl-releasing protein 2 (RASGRP2) and similar proteins; RASGRP2, also called calcium and DAG-regulated guanine nucleotide exchange factor I (CalDAG-GEFI), Cdc25-like protein (CDC25L), or F25B3.3 kinase-like protein, functions as a calcium- and DAG-regulated nucleotide exchange factor specifically activating Rap through the exchange of bound GDP for GTP. It may also activate other GTPases such as RRAS, RRAS2, NRAS, KRAS but not HRAS. RASGRP2 is also involved in aggregation of platelets and adhesion of T-lymphocytes and neutrophils probably through inside-out integrin activation, as well as in the muscarinic acetylcholine receptor M1/CHRM1 signaling pathway. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 149158727 496 GFVHNFQESNSLRPVACRHCKALILGIYKQGLKCRACGVNCHKQCKDRLSVECRRR 551
Cdd:cd20861    1 GFIHNFAERTFLRPVACRHCKNLILGIYKQGLKCRACGVNCHKQCKDHLSIECRKR 56

Ca2+-binding protein, EF-hand superfamily [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149158727 407 LEEWTSAAKPKLDQAlvvehIEKMVESVFRNFDVDGDGHISQEEFQIIRGNFPYLS-----AFGDLDQNQDGCISREEMV 481
Cdd:COG5126   52 REEFVAGMESLFEAT-----VEPFARAAFDLLDTDGDGKISADEFRRLLTALGVSEeeadeLFARLDTDGDGKISFEEFV 126

                 ...
gi 149158727 482 SYF 484
Cdd:COG5126  127 AAV 129

Guanine nucleotide exchange factor for Ras-like small GTPases. Small GTP-binding proteins of the Ras superfamily function as molecular switches in fundamental events such as signal transduction, cytoskeleton dynamics and intracellular trafficking. Guanine-nucleotide-exchange factors (GEFs) positively regulate these GTP-binding proteins in response to a variety of signals. GEFs catalyze the dissociation of GDP from the inactive GTP-binding proteins. GTP can then bind and induce structural changes that allow interaction with effectors.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149158727 150 FDHLEPMELAEHLTYLEYRSFCKILFQDYHSFVTHGCTVD---NPVLERFISLFNSVSQWVQLMILSKPTAPQRALVITH 226
Cdd:cd00155    1 FLSLDPKELAEQLTLLDFELFRKIEPFELLGSLWSKKDKNihlSPNLERFIERFNNLSNWVASEILLCTNPKKRARLLSK 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149158727 227 FVHVAEKLLQLQNFNTLMAVVGGLSHSSISRLKETHSHVSPETIKLWEGLTELVTATGNYGNYRRRLAAC--VGFRFPIL 304
Cdd:cd00155   81 FIQVAKHCRELNNFNSLMAIVSALSSSPISRLKKTWEVLSSKLKKLFEELEELVDPSRNFKNYRKLLKSVgpNPPCVPFL 160

                        170       180       190       200       210       220       230
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 149158727 305 GVHLKDLVALQLALPDWLDpaRTRLNGAKMKQLFSILEELAMVTSLRPPVQANPDLLSLLTVSLDQYQTEDELYQLSLQ 383
Cdd:cd00155  161 GVYLKDLTFLHEGNPDFLE--GNLVNFEKRRKIAEILREIRQLQSNSYELNRDEDILAFLWKLLELILNEDELYELSLE 237

protein kinase C conserved region 1 (C1 domain) found in RAS guanyl-releasing protein 2 (RASGRP2) and similar proteins; RASGRP2, also called calcium and DAG-regulated guanine nucleotide exchange factor I (CalDAG-GEFI), Cdc25-like protein (CDC25L), or F25B3.3 kinase-like protein, functions as a calcium- and DAG-regulated nucleotide exchange factor specifically activating Rap through the exchange of bound GDP for GTP. It may also activate other GTPases such as RRAS, RRAS2, NRAS, KRAS but not HRAS. RASGRP2 is also involved in aggregation of platelets and adhesion of T-lymphocytes and neutrophils probably through inside-out integrin activation, as well as in the muscarinic acetylcholine receptor M1/CHRM1 signaling pathway. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 149158727 496 GFVHNFQESNSLRPVACRHCKALILGIYKQGLKCRACGVNCHKQCKDRLSVECRRR 551
Cdd:cd20861    1 GFIHNFAERTFLRPVACRHCKNLILGIYKQGLKCRACGVNCHKQCKDHLSIECRKR 56

Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal domain (RasGef_N), also called REM domain (Ras exchanger motif). This domain is common in nucleotide exchange factors for Ras-like small GTPases and is typically found immediately N-terminal to the RasGef (Cdc25-like) domain. REM contacts the GTPase and is assumed to participate in the catalytic activity of the exchange factor. Proteins with the REM domain include Sos1 and Sos2, which relay signals from tyrosine-kinase mediated signalling to Ras, RasGRP1-4, RasGRF1,2, CNrasGEF, and RAP-specific nucleotide exchange factors, to name a few.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149158727  12 TVEELLRGCIEAFDDSgkvrDPQLVRMFLMMHPWYIPSSQLAAKLLHIYQ----------QSRKDNSNSLQVKTCHLVRY 81
Cdd:cd06224    1 TLEALIEHLTSTFDMP----DPSFVSTFLLTYRSFTTPTELLEKLIERYEiappenleynDWDKKKSKPIRLRVLNVLRT 76

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|..
gi 149158727  82 WISAFPAEFDLNPELAEQIKELKALLDQEGNRRHSSLIDIDS 123
Cdd:cd06224   77 WVENYPYDFFDDEELLELLEEFLNRLVQEGALLQELKKLLRK 118

Phorbol esters/diacylglycerol binding domain (C1 domain); This domain is also known as the Protein kinase C conserved region 1 (C1) domain.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 149158727  499 HNFQESNSLRPVACRHCKALILGIYKQGLKCRACGVNCHKQCKDRLSVECR 549
Cdd:pfam00130   1 HHFVHRNFKQPTFCDHCGEFLWGLGKQGLKCSWCKLNVHKRCHEKVPPECG 51

EF-hand, calcium binding motif; A diverse superfamily of calcium sensors and calcium signal modulators; most examples in this alignment model have 2 active canonical EF hands. Ca2+ binding induces a conformational change in the EF-hand motif, leading to the activation or inactivation of target proteins. EF-hands tend to occur in pairs or higher copy numbers.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 149158727 430 MVESVFRNFDVDGDGHISQEEF-QIIRGNFPYLS------AFGDLDQNQDGCISREEMV 481
Cdd:cd00051    1 ELREAFRLFDKDGDGTISADELkAALKSLGEGLSeeeideMIREVDKDGDGKIDFEEFL 59

transaldolase;

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 149158727 425 EHIEKMVESVFRNFDVDGDGHISQEEfqiirgnfpYLSA---FGDLDQNQDGCISREEMVS 482
Cdd:PRK12309 330 EAFTHAAQEIFRLYDLDGDGFITREE---------WLGSdavFDALDLNHDGKITPEEMRA 381

EF-hand, calcium binding motif; EF-hands are calcium-binding motifs that occur at least in pairs. Links between disease states and genes encoding EF-hands, particularly the S100 subclass, are emerging. Each motif consists of a 12 residue loop flanked on either side by a 12 residue alpha-helix. EF-hands undergo a conformational change unpon binding calcium ions.

                           10        20
                   ....*....|....*....|....
gi 149158727   431 VESVFRNFDVDGDGHISQEEFQII 454
Cdd:smart00054   2 LKEAFRLFDKDGDGKIDFEEFKDL 25

Guanine nucleotide exchange factor for Ras-like small GTPases. Small GTP-binding proteins of the Ras superfamily function as molecular switches in fundamental events such as signal transduction, cytoskeleton dynamics and intracellular trafficking. Guanine-nucleotide-exchange factors (GEFs) positively regulate these GTP-binding proteins in response to a variety of signals. GEFs catalyze the dissociation of GDP from the inactive GTP-binding proteins. GTP can then bind and induce structural changes that allow interaction with effectors.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149158727 150 FDHLEPMELAEHLTYLEYRSFCKILFQDYHSFVTHGCTVD---NPVLERFISLFNSVSQWVQLMILSKPTAPQRALVITH 226
Cdd:cd00155    1 FLSLDPKELAEQLTLLDFELFRKIEPFELLGSLWSKKDKNihlSPNLERFIERFNNLSNWVASEILLCTNPKKRARLLSK 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149158727 227 FVHVAEKLLQLQNFNTLMAVVGGLSHSSISRLKETHSHVSPETIKLWEGLTELVTATGNYGNYRRRLAAC--VGFRFPIL 304
Cdd:cd00155   81 FIQVAKHCRELNNFNSLMAIVSALSSSPISRLKKTWEVLSSKLKKLFEELEELVDPSRNFKNYRKLLKSVgpNPPCVPFL 160

                        170       180       190       200       210       220       230
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 149158727 305 GVHLKDLVALQLALPDWLDpaRTRLNGAKMKQLFSILEELAMVTSLRPPVQANPDLLSLLTVSLDQYQTEDELYQLSLQ 383
Cdd:cd00155  161 GVYLKDLTFLHEGNPDFLE--GNLVNFEKRRKIAEILREIRQLQSNSYELNRDEDILAFLWKLLELILNEDELYELSLE 237

protein kinase C conserved region 1 (C1 domain) found in RAS guanyl-releasing protein 2 (RASGRP2) and similar proteins; RASGRP2, also called calcium and DAG-regulated guanine nucleotide exchange factor I (CalDAG-GEFI), Cdc25-like protein (CDC25L), or F25B3.3 kinase-like protein, functions as a calcium- and DAG-regulated nucleotide exchange factor specifically activating Rap through the exchange of bound GDP for GTP. It may also activate other GTPases such as RRAS, RRAS2, NRAS, KRAS but not HRAS. RASGRP2 is also involved in aggregation of platelets and adhesion of T-lymphocytes and neutrophils probably through inside-out integrin activation, as well as in the muscarinic acetylcholine receptor M1/CHRM1 signaling pathway. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 149158727 496 GFVHNFQESNSLRPVACRHCKALILGIYKQGLKCRACGVNCHKQCKDRLSVECRRR 551
Cdd:cd20861    1 GFIHNFAERTFLRPVACRHCKNLILGIYKQGLKCRACGVNCHKQCKDHLSIECRKR 56

Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal motif; A subset of guanine nucleotide exchange factor for Ras-like small GTPases appear to possess this domain N-terminal to the RasGef (Cdc25-like) domain. The recent crystal structureof Sos shows that this domain is alpha-helical and plays a "purely structural role" (Nature 394, 337-343).

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149158727     7 LDKGCTVEELLRGCIEAFDDsgkvRDPQLVRMFLMMHPWYIPSSQLAAKLLHIYQ-------QSRKDNSNSLQVKTCHLV 79
Cdd:smart00229   4 LIKGGTLEALIEHLTEAFDK----ADPSFVETFLLTYRSFITTQELLQLLLYRYNaippeswVEEKVNPRRVKNRVLNIL 79

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|...
gi 149158727    80 RYWISAFPAEFDLNPELAEQIKELKALLDQE-GNRRHSSLIDI 121
Cdd:smart00229  80 RTWVENYWEDFEDDPKLISFLLEFLELVDDEkYPGLVTSLLNL 122

protein kinase C conserved region 1 (C1 domain) found in RAS guanyl-releasing protein 3 (RASGRP3) and similar proteins; RASGRP3, also called calcium and DAG-regulated guanine nucleotide exchange factor III (CalDAG-GEFIII), or guanine nucleotide exchange factor for Rap1, is a guanine nucleotide-exchange factor activating H-Ras, R-Ras and Ras-associated protein-1/2. It functions as an important mediator of signaling downstream from receptor coupled phosphoinositide turnover in B and T cells. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 149158727 496 GFVHNFQESNSLRPVACRHCKALILGIYKQGLKCRACGVNCHKQCKDRLSVECRR 550
Cdd:cd20862    5 GFIHNFQEMTYLKPTFCEHCAGFLWGIIKQGYKCKDCGVNCHKQCKDLLVLACRK 59

protein kinase C conserved region 1 (C1 domain) found in RAS guanyl-releasing protein 4 (RASGRP4) and similar proteins; RASGRP4 functions as a cation- and diacylglycerol (DAG)-regulated nucleotide exchange factor activating Ras through the exchange of bound GDP for GTP. It may function in mast cell differentiation. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 149158727 496 GFVHNFQESNSLRPVACRHCKALILGIYKQGLKCRACGVNCHKQCKDRLSVECRRR 551
Cdd:cd20863    1 GFLHNFHETTFKKPTFCDSCSGFLWGVTKQGYRCQDCGINCHKHCKDQVDVECKKR 56

second protein kinase C conserved region 1 (C1 domain) found in the family of protein kinase D (PKD); PKDs are important regulators of many intracellular signaling pathways such as ERK and JNK, and cellular processes including the organization of the trans-Golgi network, membrane trafficking, cell proliferation, migration, and apoptosis. They are activated in a PKC-dependent manner by many agents including diacylglycerol (DAG), PDGF, neuropeptides, oxidative stress, and tumor-promoting phorbol esters, among others. Mammals harbor three types of PKDs: PKD1 (or PKCmu), PKD2, and PKD3 (or PKCnu). PKDs contain N-terminal tandem cysteine-rich zinc binding C1 (PKC conserved region 1), central PH (Pleckstrin Homology), and C-terminal catalytic kinase domains. This model corresponds to the second C1 domain. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 149158727 499 HNFQESNSLRPVACRHCKALILGIYKQGLKCRACGVNCHKQCKDRLSVECR 549
Cdd:cd20796    2 HTFVVHTYTKPTVCQHCKKLLKGLFRQGLQCKDCKFNCHKKCAEKVPKDCT 52

protein kinase C conserved region 1 (C1 domain) found in Munc13-1 and similar proteins; Munc13-1, also called protein unc-13 homolog A (Unc13A), is a diacylglycerol (DAG) receptor that plays a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway. It is involved in neurotransmitter release by acting in synaptic vesicle priming prior to vesicle fusion and participates in the activity-dependent refilling of readily releasable vesicle pool (RRP). Loss of MUNC13-1 function causes microcephaly, cortical hyperexcitability, and fatal myasthenia. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 149158727 492 GGRMGFVHNFQESNSLRPVACRHCKALILGIYKQGLKCRACGVNCHKQCKDRLSVECRRR 551
Cdd:cd20858    1 PISCTTPHNFEVWTATTPTYCYECEGLLWGIARQGMRCTECGVKCHEKCQDLLNADCLQR 60

protein kinase C conserved region 1 (C1 domain) found in the Munc13 family; The Munc13 gene family encodes a family of neuron-specific, synaptic molecules that bind to syntaxin, an essential mediator of neurotransmitter release. Munc13-1 is a component of presynaptic active zones in which it acts as an essential synaptic vesicle priming protein. Munc13-2 is essential for normal release probability at hippocampal mossy fiber synapses. Munc13-3 is almost exclusively expressed in the cerebellum. It acts as a tumor suppressor and plays a critical role in the formation of release sites with calcium channel nanodomains. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 149158727 499 HNFQESNSLRPVACRHCKALILGIYKQGLKCRACGVNCHKQCKDRLSVECRRR 551
Cdd:cd20807    1 HNFEVWTATTPTYCYECEGLLWGIARQGVRCTECGVKCHEKCKDLLNADCLQR 53

second protein kinase C conserved region 1 (C1 domain) found in novel protein kinase C (nPKC) theta, delta, and similar proteins; PKCs are classified into three groups (classical, atypical, and novel) depending on their mode of activation and the structural characteristics of their regulatory domain. nPKCs are calcium-independent, but require DAG (1,2-diacylglycerol) and phosphatidylserine (PS) for activity. PKC-theta is selectively expressed in T-cells and plays an important and non-redundant role in several aspects of T-cell biology. PKC-delta plays a role in cell cycle regulation and programmed cell death in many cell types. Members of this family contain two copies of C1 domain. This model corresponds to the second one. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 149158727 499 HNFQESNSLRPVACRHCKALILGIYKQGLKCRACGVNCHKQCKDRLSVEC 548
Cdd:cd20837    1 HRFKVYNYMSPTFCDHCGSLLWGLFRQGLKCEECGMNVHHKCQKKVANLC 50

protein kinase C conserved region 1 (C1 domain) found in uncharacterized proteins similar to myotubularin-related proteins; The family includes a group of uncharacterized proteins that show high sequence similarity to vertebrate myotubularin-related proteins (MTMRs), such as MTMR5 and MTMR13. MTMRs may function as guanine nucleotide exchange factors (GEFs). Vertebrate MTMR5 and MTMR13 contain an N-terminal DENN domain, a PH-GRAM domain, an inactive PTP domain, a SET interaction domain, a coiled-coil domain, and a C-terminal PH domain. Members of this family contain these domains and have an additional C1 domain. This model corresponds to the C1 domain. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 149158727 499 HNFQESNSLRPVACRHCKALILGIYKQGLKCRACGVNCHKQCKDRLSVECRR 550
Cdd:cd20828    6 HNFEPHSFVTPTNCDYCLQILWGIVKKGMKCSECGYNCHEKCQPQVPKQCSK 57

protein kinase C conserved region 1 (C1 domain) found in Munc13-2, Munc13-3 and similar proteins; Munc13-2, also called protein unc-13 homolog B (Unc13B), plays a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway. It is involved in neurotransmitter release by acting in synaptic vesicle priming prior to vesicle fusion and participates in the activity-dependent refilling of readily releasable vesicle pool (RRP). Munc13-2 is essential for normal release probability at hippocampal mossy fiber synapses. Munc13-3 is almost exclusively expressed in the cerebellum. It acts as a tumor suppressor and plays a critical role in the formation of release sites with calcium channel nanodomains. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 149158727 499 HNFQESNSLRPVACRHCKALILGIYKQGLKCRACGVNCHKQCKDRLSVECRRRAQSVSLEGSA 561
Cdd:cd20859   20 HNFEVWTATTPTYCYECEGLLWGIARQGMRCSECGVKCHEKCQDLLNADCLQRAAEKSSKHGA 82

second protein kinase C conserved region 1 (C1 domain) found in novel protein kinase C (nPKC) epsilon, eta, and similar proteins; PKCs are classified into three groups (classical, atypical, and novel) depending on their mode of activation and the structural characteristics of their regulatory domain. nPKCs are calcium-independent, but require DAG (1,2-diacylglycerol) and phosphatidylserine (PS) for activity. PKC-epsilon has been shown to behave as an oncoprotein. Its overexpression contributes to neoplastic transformation depending on the cell type. It contributes to oncogenesis by inducing disordered cell growth and inhibiting cell death. It also plays a role in tumor invasion and metastasis. PKC-epsilon has also been found to confer cardioprotection against ischemia and reperfusion-mediated damage. Other cellular functions include the regulation of gene expression, cell adhesion, and cell motility. PKC-eta is predominantly expressed in squamous epithelia, where it plays a crucial role in the signaling of cell-type specific differentiation. It is also expressed in pro-B cells and early-stage thymocytes, and acts as a key regulator in early B-cell development. PKC-eta increases glioblastoma multiforme (GBM) proliferation and resistance to radiation, and is being developed as a therapeutic target for the management of GBM. Members of this family contain two copies of C1 domain. This model corresponds to the second one. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|...
gi 149158727 499 HNFQESNSLRPVACRHCKALILGIYKQGLKCRACGVNCHKQCK 541
Cdd:cd20838    3 HRFSVHNYKRPTFCDHCGSLLYGLYKQGLQCKVCKMNVHKRCQ 45

second protein kinase C conserved region 1 (C1 domain) found in protein kinase D3 (PKD3) and similar proteins; PKD3 is also called PRKD3, PRKCN, serine/threonine-protein kinase D3 (nPKC-D3), protein kinase C nu type (nPKC-nu), or protein kinase EPK2. It converts transient diacylglycerol (DAG) signals into prolonged physiological effects, downstream of PKC. It is involved in the regulation of the cell cycle by modulating microtubule nucleation and dynamics. PKD3 acts as a key mediator in several cancer development signaling pathways. PKD3 contains N-terminal tandem cysteine-rich zinc binding C1 (PKC conserved region 1), central PH (Pleckstrin Homology), and C-terminal catalytic kinase domains. This model corresponds to the second C1 domain. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 149158727 494 RMGFVHNFQESNSLRPVACRHCKALILGIYKQGLKCRACGVNCHKQCKDRLSVECrrrAQSVSLEGSAPSP 564
Cdd:cd20844    1 RVKVPHTFAVHSYTRPTICQYCKRLLKGLFRQGMQCKDCRFNCHKRCASKVPRDC---LGEVTFNGEPASP 68

Ca2+-binding protein, EF-hand superfamily [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149158727 407 LEEWTSAAKPKLDQAlvvehIEKMVESVFRNFDVDGDGHISQEEFQIIRGNFPYLS-----AFGDLDQNQDGCISREEMV 481
Cdd:COG5126   52 REEFVAGMESLFEAT-----VEPFARAAFDLLDTDGDGKISADEFRRLLTALGVSEeeadeLFARLDTDGDGKISFEEFV 126

                 ...
gi 149158727 482 SYF 484
Cdd:COG5126  127 AAV 129

first protein kinase C conserved region 1 (C1 domain) found in protein kinase D (PKD) and similar proteins; PKD is also called PKD1, PRKD1, protein kinase C mu type (nPKC-mu), PRKCM, serine/threonine-protein kinase D1, or nPKC-D1. It is a serine/threonine-protein kinase that converts transient diacylglycerol (DAG) signals into prolonged physiological effects downstream of PKC, and is involved in the regulation of MAPK8/JNK1 and Ras signaling, Golgi membrane integrity and trafficking, cell survival through NF-kappa-B activation, cell migration, cell differentiation by mediating HDAC7 nuclear export, cell proliferation via MAPK1/3 (ERK1/2) signaling, and plays a role in cardiac hypertrophy, VEGFA-induced angiogenesis, genotoxic-induced apoptosis and flagellin-stimulated inflammatory response. PKD contains N-terminal tandem cysteine-rich zinc binding C1 (PKC conserved region 1), central PH (Pleckstrin Homology), and C-terminal catalytic kinase domains. This model corresponds to the first C1 domain. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 149158727 497 FVHNFQEsnslrPVACRHCKALILGIYKQGLKCRACGVNCHKQCKDRLSVEC----RRRAQSVSLEG 559
Cdd:cd20839   11 FVHSYRA-----PAFCDHCGEMLWGLVRQGLKCEGCGLNYHKRCAFKIPNNCsgvrKRRLSNVSLTG 72

first protein kinase C conserved region 1 (C1 domain) found in classical (or conventional) protein kinase C (cPKC), novel protein kinase C (nPKC), and similar proteins; PKCs are classified into three groups (classical, atypical, and novel) depending on their mode of activation and the structural characteristics of their regulatory domains. PKCs undergo three phosphorylations in order to take mature forms. In addition, cPKCs depend on calcium, DAG (1,2-diacylglycerol), and in most cases, phosphatidylserine (PS) for activation. nPKCs are calcium-independent, but require DAG and PS for activity, while atypical PKCs (aPKCs) only require PS. PKCs phosphorylate and modify the activities of a wide variety of cellular proteins including receptors, enzymes, cytoskeletal proteins, transcription factors, and other kinases. They play a central role in signal transduction pathways that regulate cell migration and polarity, proliferation, differentiation, and apoptosis. This family includes classical PKCs (cPKCs) and novel PKCs (nPKCs). There are four cPKC isoforms (named alpha, betaI, betaII, and gamma) and four nPKC isoforms (delta, epsilon, eta, and theta). Members of this family contain two copies of the C1 domain. This model corresponds to the first one. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 149158727 499 HNFQESNSLRPVACRHCKALILGIYKQGLKCRACGVNCHKQCKDRLSVEC 548
Cdd:cd20792    2 HKFVATFFKQPTFCSHCKDFIWGLGKQGYQCQVCRFVVHKRCHEYVVFKC 51

protein kinase C conserved region 1 (C1 domain) found in male germ cell RacGap (MgcRacGAP) and similar proteins; MgcRacGAP, also called Rac GTPase-activating protein 1 (RACGAP1) or protein CYK4, plays an important dual role in cytokinesis: i) it is part of centralspindlin-complex, together with the mitotic kinesin MKLP1, which is critical for the structure of the central spindle by promoting microtuble bundling; and ii) after phosphorylation by aurora B, MgcRacGAP becomes an effective regulator of RhoA and plays an important role in the assembly of the contractile ring and the initiation of cytokinesis. MgcRacGAP-like proteins contain an N-terminal C1 domain, and a C-terminal RhoGAP domain. This model corresponds to the C1 domain. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 149158727 498 VHNFQESNSLRPVACRHCKALIlGIYKQGLKCRACGVNCHKQCKDRLSVEC 548
Cdd:cd20821    2 PHRFVSKTVIKPETCVVCGKRI-KFGKKALKCKDCRVVCHPDCKDKLPLPC 51

protein kinase C conserved region 1 (C1 domain) found in the myotubularin-related protein Sbf and similar proteins; This group includes Drosophila melanogaster SET domain binding factor (Sbf), the single homolog of human MTMR5/MTMR13, and similar proteins, that show high sequence similarity to vertebrate myotubularin-related proteins (MTMRs) which may function as guanine nucleotide exchange factors (GEFs). Sbf is a pseudophosphatase that coordinates both phosphatidylinositol 3-phosphate (PI(3)P) turnover and Rab21 GTPase activation in an endosomal pathway that controls macrophage remodeling. It also functions as a GEF that promotes Rab21 GTPase activation associated with PI(3)P endosomes. Vertebrate MTMR5 and MTMR13 contain an N-terminal DENN domain, a PH-GRAM domain, an inactive PTP domain, a SET interaction domain, a coiled-coil domain, and a C-terminal PH domain. Members of this family contain these domains and have an additional C1 domain. This model corresponds to the C1 domain. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 149158727 499 HNFQESNSLRPVACRHCKALILGIYKQGLKCRACGVNCHKQCKDRLSVECRR 550
Cdd:cd20827    2 HRFEKHNFTTPTYCDYCSSLLWGLVKTGMRCADCGYSCHEKCLEHVPKNCTK 53

second protein kinase C conserved region 1 (C1 domain) found in the classical (or conventional) protein kinase C (cPKC) family; PKCs are classified into three groups (classical, atypical, and novel) depending on their mode of activation and the structural characteristics of their regulatory domain. cPKCs are potent kinases for histones, myelin basic protein, and protamine. They depend on calcium, DAG (1,2-diacylglycerol), and in most cases, phosphatidylserine (PS) for activation. There are four cPKC isoforms, named alpha, betaI, betaII, and gamma. PKC-alpha is expressed in many tissues and is associated with cell proliferation, apoptosis, and cell motility. It plays a role in the signaling of the growth factors PDGF, VEGF, EGF, and FGF. Abnormal levels of PKC-alpha have been detected in many transformed cell lines and several human tumors. In addition, PKC-alpha is required for HER2 dependent breast cancer invasion. The PKC beta isoforms (I and II), generated by alternative splicing of a single gene, are preferentially activated by hyperglycemia-induced DAG (1,2-diacylglycerol) in retinal tissues. This is implicated in diabetic microangiopathy such as ischemia, neovascularization, and abnormal vasodilator function. PKC-beta also plays an important role in VEGF signaling. In addition, glucose regulates proliferation in retinal endothelial cells via PKC-betaI. PKC-beta is also being explored as a therapeutic target in cancer. It contributes to tumor formation and is involved in the tumor host mechanisms of inflammation and angiogenesis. PKC-gamma is mainly expressed in neuronal tissues. It plays a role in protection from ischemia. Members of this family contain two copies of C1 domain. This model corresponds to the second one. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|...
gi 149158727 499 HNFQESNSLRPVACRHCKALILGIYKQGLKCRACGVNCHKQCK 541
Cdd:cd20836    1 HKFKVHTYSSPTFCDHCGSLLYGLIHQGMKCDTCDMNVHKRCV 43

protein kinase C conserved region 1 (C1 domain) found in SH3 and cysteine-rich domain-containing protein 2 (Stac2) and similar proteins; Stac2, also called 24b2/Stac2, or Src homology 3 and cysteine-rich domain-containing protein 2, plays a redundant role in promoting the expression of calcium channel CACNA1S at the cell membrane, and thereby contributes to increased channel activity. It slows down the inactivation rate of the calcium channel CACNA1C. Stac2 contains a cysteine-rich C1 domain and one SH3 domain at the C-terminus. This model corresponds to the C1 domain. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*..
gi 149158727 499 HNFQESNSLRPVACRHCKALILGIYKQGLKCRACGVNCHKQCKDRLS 545
Cdd:cd20881    6 HSFQEHVFKKPSPCELCHQMIVGNSKQGLRCKMCKVSVHLWCSEEVS 52

protein kinase C conserved region 1 (C1 domain) found in the chimaerin family; Chimaerins are a family of phorbolester- and diacylglycerol-responsive GTPase activating proteins (GAPs) specific for the Rho-like GTPase Rac. Alpha1-chimerin (formerly known as N-chimerin) and alpha2-chimerin are alternatively spliced products of a single gene, as are beta1- and beta2-chimerin. Alpha1- and beta1-chimerin have a relatively short N-terminal region that does not encode any recognizable domains, whereas alpha2- and beta2-chimerin both include a functional SH2 domain that can bind to phosphotyrosine motifs within receptors. All the isoforms contain a GAP domain with specificity in vitro for Rac1 and a diacylglycerol (DAG)-binding C1 domain which allows them to translocate to membranes in response to DAG signaling and anchors them in close proximity to activated Rac. This model corresponds to the C1 domain. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 149158727 499 HNFQESNSLRPVACRHCKALILGIYKQGLKCRACGVNCHKQCKDRLSVEC 548
Cdd:cd20806    2 HNFKVHTFKGPHWCDYCGNFMWGLIAQGVKCEDCGFNAHKQCSKLVPHDC 51

first protein kinase C conserved region 1 (C1 domain) found in protein kinase D2 (PKD2) and similar proteins; PKD2, also called PRKD2, HSPC187, or serine/threonine-protein kinase D2 (nPKC-D2), is a serine/threonine-protein kinase that converts transient diacylglycerol (DAG) signals into prolonged physiological effects downstream of PKC, and is involved in the regulation of cell proliferation via MAPK1/3 (ERK1/2) signaling, oxidative stress-induced NF-kappa-B activation, inhibition of HDAC7 transcriptional repression, signaling downstream of T-cell antigen receptor (TCR) and cytokine production, and plays a role in Golgi membrane trafficking, angiogenesis, secretory granule release and cell adhesion. PKD2 contains N-terminal tandem cysteine-rich zinc binding C1 (PKC conserved region 1), central PH (Pleckstrin Homology), and C-terminal catalytic kinase domains. This model corresponds to the first C1 domain. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 149158727 509 PVACRHCKALILGIYKQGLKCRACGVNCHKQCKDRLSVEC----RRRAQSVSL 557
Cdd:cd20840   21 PAFCDHCGEMLFGLVRQGLKCDGCGLNYHKRCAFSIPNNCsgarKRRLSSTSL 73

protein kinase C conserved region 1 (C1 domain) found in myotonic dystrophy kinase-related Cdc42-binding kinase alpha (MRCK alpha) and similar proteins; MRCK alpha, also called Cdc42-binding protein kinase alpha, DMPK-like alpha, or myotonic dystrophy protein kinase-like alpha, is a serine/threonine-protein kinase expressed ubiquitously in many tissues. It plays a role in the regulation of peripheral actin reorganization and neurite outgrowth. It may also play a role in the transferrin iron uptake pathway. MRCK alpha is an important downstream effector of Cdc42 and plays a role in the regulation of cytoskeleton reorganization and cell migration. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 149158727 499 HNFQESNSLRPVACRHCKALILGIYKQGLKCRACGVNCHKQCKDRLSVEC 548
Cdd:cd20864    3 HQFVVKSFTTPTKCNQCTSLMVGLIRQGCTCEVCGFSCHVTCADKAPSVC 52

protein kinase C conserved region 1 (C1 domain) found in the Ras association domain-containing protein 1 (RASSF1)-like family; The RASSF1-like family includes RASSF1 and RASSF5. RASSF1 and RASSF5 are members of a family of RAS effectors, of which there are currently 8 members (RASSF1-8), all containing a Ras-association (RA) domain of the Ral-GDS/AF6 type. RASSF1 has eight transcripts (A-H) arising from alternative splicing and differential promoter usage. RASSF1A and 1C are the most extensively studied RASSF1; both are localized to microtubules and involved in the regulation of growth and migration. RASSF1 is a potential tumor suppressor that is required for death receptor-dependent apoptosis. RASSF5, also called new ras effector 1 (NORE1), or regulator for cell adhesion and polarization enriched in lymphoid tissues (RAPL), is expressed as three transcripts (A-C) via differential promoter usage and alternative splicing. RASSF5A is a pro-apoptotic Ras effector and functions as a Ras regulated tumor suppressor. RASSF5C is regulated by Ras related protein and modulates cellular adhesion. RASSF5 is a potential tumor suppressor that seems to be involved in lymphocyte adhesion by linking RAP1A activation upon T-cell receptor or chemokine stimulation to integrin activation. RASSF1 and RASSF5 contain a C1 domain, which is descibed in this model. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 149158727 499 HNFQESNSLRPVACRHCKALILGIYKQGLKCRACGVNCHKQCKDRLSVECR 549
Cdd:cd20820    2 HRFVPLELEQPTWCDLCGSVILGLFRKCLRCANCKMTCHPRCRSLVCLTCR 52

first protein kinase C conserved region 1 (C1 domain) found in type II diacylglycerol kinases; Diacylglycerol (DAG) kinase (EC 2.7.1.107) is a lipid kinase that phosphorylates diacylglycerol to form phosphatidic acid. Type II DAG kinases (DGKs) contain pleckstrin homology (PH) and sterile alpha motifs (SAM) domains, in addition to C1 and catalytic domains that are present in all DGKs. The SAM domain mediates oligomerization of type II DGKs. Three DGK isozymes (delta, eta and kappa) are classified as type II. DAG kinase delta, also called 130 kDa DAG kinase, or diglyceride kinase delta (DGK-delta), is a residential lipid kinase in the endoplasmic reticulum. It promotes lipogenesis and is involved in triglyceride biosynthesis. DAG kinase eta, also called diglyceride kinase eta (DGK-eta), plays a key role in promoting cell growth. The DAG kinase eta gene, DGKH, is a replicated risk gene of bipolar disorder (BPD). DAG kinase kappa is also called diglyceride kinase kappa (DGK-kappa) or 142 kDa DAG kinase. Members of this family contain two copies of the C1 domain. This model corresponds to the first one. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 149158727 499 HNFQESNSLRPVACRHCKALILGIYKQGLKCRACGVNCHKQCKDRLSVECR 549
Cdd:cd20800    5 HNWYACSHARPTYCNVCREALSGVTSHGLSCEVCKFKAHKRCAVKAPNNCK 55

protein kinase C conserved region 1 (C1 domain) found in VAV2 protein; VAV2 is widely expressed and functions as a guanine nucleotide exchange factor (GEF) for RhoA, RhoB and RhoG and also activates Rac1 and Cdc42. It is implicated in many cellular and physiological functions including blood pressure control, eye development, neurite outgrowth and branching, EGFR endocytosis and degradation, and cell cluster morphology, among others. It has been reported to associate with Nek3. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. This model corresponds to the C1 domain. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|..
gi 149158727 499 HNFQESNSLRPVACRHCKALILGIYKQGLKCRACGVNCHKQC 540
Cdd:cd20868    6 HNFQMYTFDKTTNCKACKMLLRGTFYQGYYCSKCGAGAHKEC 47

protein kinase C conserved region 1 (C1 domain) found in beta-chimaerin and similar proteins; Beta-chimaerin, also called beta-chimerin (BCH) or Rho GTPase-activating protein 3 (ARHGAP3), is a GTPase-activating protein (GAP) for p21-rac. Insufficient expression of beta-2 chimaerin is expected to lead to higher Rac activity and could therefore play a role in the progression from low-grade to high-grade tumors. Beta-chimaerin contains a functional SH2 domain that can bind to phosphotyrosine motifs within receptors, a GAP domain with specificity in vitro for Rac1 and a diacylglycerol (DAG)-binding C1 domain which allows them to translocate to membranes in response to DAG signaling and anchors them in close proximity to activated Rac. This model corresponds to the C1 domain. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 149158727 498 VHNFQESNSLRPVACRHCKALILGIYKQGLKCRACGVNCHKQCKDRLSVECR 549
Cdd:cd20857    5 AHNFKVHTFRGPHWCEYCANFMWGLIAQGVRCSDCGLNVHKQCSKHVPNDCQ 56

first protein kinase C conserved region 1 (C1 domain) found in the classical (or conventional) protein kinase C (cPKC) family; PKCs are classified into three groups (classical, atypical, and novel) depending on their mode of activation and the structural characteristics of their regulatory domains. cPKCs are potent kinases for histones, myelin basic protein, and protamine. They depend on calcium, DAG (1,2-diacylglycerol), and in most cases, phosphatidylserine (PS) for activation. There are four cPKC isoforms, named alpha, betaI, betaII, and gamma. PKC-alpha is expressed in many tissues and is associated with cell proliferation, apoptosis, and cell motility. It plays a role in the signaling of the growth factors PDGF, VEGF, EGF, and FGF. Abnormal levels of PKC-alpha have been detected in many transformed cell lines and several human tumors. In addition, PKC-alpha is required for HER2 dependent breast cancer invasion. The PKC beta isoforms (I and II), generated by alternative splicing of a single gene, are preferentially activated by hyperglycemia-induced DAG (1,2-diacylglycerol) in retinal tissues. This is implicated in diabetic microangiopathy such as ischemia, neovascularization, and abnormal vasodilator function. PKC-beta also plays an important role in VEGF signaling. In addition, glucose regulates proliferation in retinal endothelial cells via PKC-betaI. PKC-beta is also being explored as a therapeutic target in cancer. It contributes to tumor formation and is involved in the tumor host mechanisms of inflammation and angiogenesis. PKC-gamma is mainly expressed in neuronal tissues. It plays a role in protection from ischemia. Members of this family contain two copies of the C1 domain. This model corresponds to the first one. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.