Kruppel-like factor (KLF) 9, KLF13, KLF14, KLF16, and similar proteins; Kruppel/Krueppel-like transcription factors (KLFs) belong to a family of proteins, called the Specificity Protein (SP)/KLF family, characterized by a C-terminal DNA-binding domain of 81 amino acids consisting of three Kruppel-like C2H2 zinc fingers. These factors bind to a loose consensus motif, namely NNRCRCCYY (where N is any nucleotide; R is A/G, and Y is C/T), such as the recurring motifs in GC and GT boxes (5'-GGGGCGGGG-3' and 5-GGTGTGGGG-3') that are present in promoters and more distal regulatory elements of mammalian genes. Members of the KLF family can act as activators or repressors of transcription depending on cell and promoter context. KLFs regulate various cellular functions, such as proliferation, differentiation, and apoptosis, as well as the development and homeostasis of several types of tissue. KLF9, KLF10, KLF11, KLF13, KLF14, and KLF16 share a conserved alpha-helical motif AA/VXXL that mediates their binding to Sin3A and their activities as transcriptional repressors. In addition to the C-terminal DNA-binding domain, each KLF also has a unique N-terminal activation/repression domain that confers specificity and allows it to bind specifically to a certain partner, leading to distinct activities in vivo. This model represents the related N-terminal domains of KLF9, KLF13, KLF14, KLF16, and similar proteins.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 21624641  56 GSSGEQTGPEAPGSSNNPPSTGEGPAGAPPASPGPASSrQSHRHRP 101
Cdd:cd21576 142 SSFGAPAIPSAPAAPGAPAVSGEVPGGAPGAGPAPAAG-PAPRRRP 186

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        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 21624641 210 ELRIAFREFDRDRDGRITVAELREAVPALlGEPLAGPELDEMLREVDLNGDGTVDFDEFVMMLS 273
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKSL-GEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 21624641   210 ELRIAFREFDRDRDGRITVAELREAV-PALLGEPLAGPELDEMLREVDLNGDGTVDFDEFV 269
Cdd:pfam13499   3 KLKEAFKLLDSDGDGYLDVEELKKLLrKLEEGEPLSDEEVEELFKEFDLDKDGRISFEEFL 63

N-terminal domain of Kruppel-like factor 14; Kruppel-like factor 14 (KLF14; also known as Krueppel-like factor 14 or basic transcription element-binding protein 5/BTEB5) is a protein that in humans is encoded by the KLF14 gene. KLF14 regulates the transcription of various genes, including TGFbetaRII (the type II receptor for TGFbeta). KLF14 is expressed in many tissues, lacks introns, and is subject to parent-specific expression. It also appears to be a master regulator of gene expression in adipose tissue. KLF14 is associated with coronary artery disease, hypercholesterolemia, and type 2 diabetes. KLF9, KLF10, KLF11, KLF13, KLF14, and KLF16 share a conserved alpha-helical motif AA/VXXL that mediates their binding to Sin3A and their activities as transcriptional repressors. KLF14 belongs to a family of proteins, called the Specificity Protein (SP)/KLF family, characterized by a C-terminal DNA-binding domain of 81 amino acids consisting of three Kruppel-like C2H2 zinc fingers. These factors bind to a loose consensus motif, namely NNRCRCCYY (where N is any nucleotide; R is A/G, and Y is C/T), such as the recurring motifs in GC and GT boxes (5'-GGGGCGGGG-3' and 5-GGTGTGGGG-3') that are present in promoters and more distal regulatory elements of mammalian genes. Members of the KLF family can act as activators or repressors of transcription depending on cell and promoter context. KLFs regulate various cellular functions, such as proliferation, differentiation, and apoptosis, as well as the development and homeostasis of several types of tissue. In addition to the C-terminal DNA-binding domain, each KLF also has a unique N-terminal activation/repression domain that confers specificity and allows it to bind specifically to a certain partner, leading to distinct activities in vivo. This model represents the N-terminal domain of KLF14.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 21624641  56 GSSGEQTGPEAPGSSNNPPSTGEGPAGAPPASPGPASSrQSHRHRP 101
Cdd:cd21576 142 SSFGAPAIPSAPAAPGAPAVSGEVPGGAPGAGPAPAAG-PAPRRRP 186

centrin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21624641  120 FGKDRELGPEELDELQAAFEEFDTDRDGYISHRELGDCMRTLGYMPTEMELLEVSQHIKMRMGGRVDFEEFVELIGPKL- 198
Cdd:PTZ00183   5 RSERPGLTEDQKKEIREAFDLFDTDGSGTIDPKELKVAMRSLGFEPKKEEIKQMIADVDKDGSGKIDFEEFLDIMTKKLg 84

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21624641  199 ----REETAHMlgvrelriaFREFDRDRDGRITVAELREaVPALLGEPLAGPELDEMLREVDLNGDGTVDFDEFVMMLSR 274
Cdd:PTZ00183  85 erdpREEILKA---------FRLFDDDKTGKISLKNLKR-VAKELGETITDEELQEMIDEADRNGDGEISEEEFYRIMKK 154

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21624641 129 EELDELQAAFEEFDTDRDGYISHRELGDCMRtlGYMPTEMELLEVSQHikmrmgGRVDFEEFVELIgPKLREETAHmlgv 208
Cdd:COG5126   2 LQRRKLDRRFDLLDADGDGVLERDDFEALFR--RLWATLFSEADTDGD------GRISREEFVAGM-ESLFEATVE---- 68

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 21624641 209 RELRIAFREFDRDRDGRITVAELREAVPALlgePLAGPELDEMLREVDLNGDGTVDFDEFV 269
Cdd:COG5126  69 PFARAAFDLLDTDGDGKISADEFRRLLTAL---GVSEEEADELFARLDTDGDGKISFEEFV 126

Penta-EF hand, calcium binding motifs, found in Group I PEF proteins; The family corresponds to Group I PEF proteins that have been found not only in higher animals but also in lower animals, plants, fungi and protists. Group I PEF proteins include apoptosis-linked gene 2 protein (ALG-2), peflin and similar proteins. ALG-2, also termed programmed cell death protein 6 (PDCD6), is a widely expressed calcium-binding modulator protein associated with cell proliferation and death, as well as cell survival. It forms a homodimer in the cell or a heterodimer with its closest paralog peflin. Among the PEF proteins, ALG-2 can bind three Ca2+ ions through its EF1, EF3, and EF5 hands, where it is unique in that its EF5 hand binds Ca2+ ion in a canonical coordination. Peflin is a ubiquitously expressed 30-kD PEF protein containing five EF-hand motifs in its C-terminal domain and a longer N-terminal hydrophobic domain (NHB domain) than any other member of the PEF family. The NHB domain harbors nine repeats of a nonapeptide (A/PPGGPYGGP). Peflin may modulate the function of ALG-2 in Ca2+ signaling. It exists only as a heterodimer with ALG-2, and binds two Ca2+ ions through its EF1 and EF3 hands. Its additional EF5 hand is unpaired and does not bind Ca2+ ion but mediates the heterodimerization with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21624641 115 LLNRVFGKDR--ELGPEE-------LDELQAAFEEFDTDRDGYISHRELGDCMRTLGY-MPTEMELLEVSQHIKmRMGGR 184
Cdd:cd16180  41 LMINMFDRDRsgTINFDEfvglwkyIQDWRRLFRRFDRDRSGSIDFNELQNALSSFGYrLSPQFVQLLVRKFDR-RRRGS 119

                        90       100       110       120
                ....*....|....*....|....*....|....*....|...
gi 21624641 185 VDFEEFVELigpklreetahMLGVRELRIAFREFDRDRDGRIT 227
Cdd:cd16180 120 ISFDDFVEA-----------CVTLKRLTDAFRKYDTNRTGYAT 151

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        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 21624641 133 ELQAAFEEFDTDRDGYISHRELGDCMRTLGYMPTEMELLEVsqhikMRMG-----GRVDFEEFVELI 194
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEM-----IREVdkdgdGKIDFEEFLELM 62

EF-hand, calcium binding motif, found in homologs of mammalian apoptosis-linked gene 2 protein (ALG-2); The family includes some homologs of mammalian apoptosis-linked gene 2 protein (ALG-2) mainly found in lower eukaryotes, such as a parasitic protist Leishmarua major and a cellular slime mold Dictyostelium discoideum. These homologs contains five EF-hand motifs. Due to the presence of unfavorable residues at the Ca2+-coordinating positions, their non-canonical EF4 and EF5 hands may not bind Ca2+. Two Dictyostelium PEF proteins are the prototypes of this family. They may bind to cytoskeletal proteins and/or signal-transducing proteins localized to detergent-resistant membranes named lipid rafts, and occur as monomers or weak homo- or heterodimers like ALG-2. They can serve as a mediator for Ca2+ signaling-related Dictyostehum programmed cell death (PCD).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21624641 133 ELQAAFEEFDTDRDGYISHRELGDcMRTLGYMPTEMELleVSQHIKM---RMGGRVDFEEFVELigpklreetaH--MLG 207
Cdd:cd16185   1 ELRQWFRAVDRDRSGSIDVNELQK-ALAGGGLLFSLAT--AEKLIRMfdrDGNGTIDFEEFAAL----------HqfLSN 67

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 21624641 208 VRElriAFREFDRDRDGRITVAELREAVpALLGEPLAGPELDEMLREVDLNGDGTVDFDEFVMM 271
Cdd:cd16185  68 MQN---GFEQRDTSRSGRLDANEVHEAL-AASGFQLDPPAFQALFRKFDPDRGGSLGFDDYIEL 127

EF-hand motif found in eukaryotic phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11) isozymes; PI-PLC isozymes are signaling enzymes that hydrolyze the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which goes on to phosphorylate other molecules, leading to altered cellular activity. Calcium is required for the catalysis. This family corresponds to the four EF-hand motifs containing PI-PLC isozymes, including PI-PLC-beta (1-4), -gamma (1-2), -delta (1,3,4), -epsilon (1), -zeta (1), eta (1-2). Lower eukaryotes such as yeast and slime molds contain only delta-type isozymes. In contrast, other types of isoforms present in higher eukaryotes. This family also includes 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase 1 (PLC1) from fungi. Some homologs from plants contain only two atypical EF-hand motifs and they are not included. All PI-PLC isozymes except sperm-specific PI-PLC-zeta share a core set of domains, including an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core, and a single C2 domain. PI-PLC-zeta lacks the PH domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. Most of EF-hand motifs found in PI-PLCs consist of a helix-loop-helix structure, but lack residues critical to metal binding. Moreover, the EF-hand region of most of PI-PLCs may have an important regulatory function, but it has yet to be identified. However, PI-PLC-zeta is a key exception. It is responsible for Ca2+ oscillations in fertilized oocytes and exhibits a high sensitivity to Ca2+ mediated through its EF-hand domain. In addition, PI-PLC-eta2 shows a canonical EF-loop directing Ca2+-sensitivity and thus can amplify transient Ca2+ signals. Also it appears that PI-PLC-delta1 can regulate the binding of PH domain to PIP2 in a Ca2+-dependent manner through its functionally important EF-hand domains. PI-PLCs can be activated by a variety of extracellular ligands, such as growth factors, hormones, cytokines and lipids. Their activation has been implicated in tumorigenesis and/or metastasis linked to migration, proliferation, growth, inflammation, angiogenesis and actin cytoskeleton reorganization. PI-PLC-beta isozymes are activated by G-protein coupled receptor (GPCR) through different mechanisms. However, PI-PLC-gamma isozymes are activated by receptor tyrosine kinase (RTK), such as Rho and Ras GTPases. In contrast, PI-PLC-epsilon are activated by both GPCR and RTK. PI-PLC-delta1 and PLC-eta 1 are activated by GPCR-mediated calcium mobilization. The activation mechanism for PI-PLC-zeta remains unclear.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 21624641 211 LRIAFREFDRDRDGRITVAELREAVPALLGePLAGPELDEMLREVDLNGDGTVDFDEFVMMLSRH 275
Cdd:cd15898   2 LRRQWIKADKDGDGKLSLKEIKKLLKRLNI-RVSEKELKKLFKEVDTNGDGTLTFDEFEELYKSL 65

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21624641 134 LQAAFEEFDTDRDGYISHRELGDCMRTLGYMPTEMELLEVSQHIKMRMGGRVDFEEFVELIgpklreeTAHMLGVRELRI 213
Cdd:COG5126  35 WATLFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDLLDTDGDGKISADEFRRLL-------TALGVSEEEADE 107

                        90       100
                ....*....|....*....|..
gi 21624641 214 AFREFDRDRDGRITVAELREAV 235
Cdd:COG5126 108 LFARLDTDGDGKISFEEFVAAV 129

EF-hand, calcium binding motif, found in reticulocalbin-2 (RCN2) mainly from protostomes; This family corresponds to a group of uncharacterized RCN2-like proteins, which are mainly found in protostomes. Although their biological function remains unclear, they show high sequence similarity with RCN2 (also known as E6BP or TCBP-49), which is an endoplasmic reticulum resident low-affinity Ca2+-binding protein that has been implicated in immunity, redox homeostasis, cell cycle regulation and coagulation. Members in this family contain six copies of the EF-hand Ca2+-binding motif, but may lack a C-terminal His-Asp-Glu-Leu (HDEL) tetrapeptide that is required for retention of RCN2 in the endoplasmic reticulum (ER).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21624641 130 ELDELQAA--FEEFDTDRDGYISHRELgdCMRTLGYMPTEME----------LLEVSQHIKMRMG------GRVDFEEFV 191
Cdd:cd16227  68 MLDEEEANerFEEADEDGDGKVTWEEY--LADSFGYDDEDNEemikdsteddLKLLEDDKEMFEAadlnkdGKLDKTEFS 145

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21624641 192 ELIGPklrEETAHMLGVrELRIAFREFDRDRDGRITVAELreavpalLGEpLAGP--------ELDEMLREVDLNGDGTV 263
Cdd:cd16227 146 AFQHP---EEYPHMHPV-LIEQTLRDKDKDNDGFISFQEF-------LGD-RAGHedkewllvEKDRFDEDYDKDGDGKL 213

                ....
gi 21624641 264 DFDE 267
Cdd:cd16227 214 DGEE 217

EF-hand, calcium binding motif, found in secretagogin (SCGN); SCGN is a six EF-hand calcium-binding protein expressed in neuroendocrine, pancreatic endocrine and retinal cells. It plays a crucial role in cell apoptosis, receptor signaling and differentiation. It is also involved in vesicle secretion through binding to various proteins, including interacts with SNAP25, SNAP23, DOC2alpha, ARFGAP2, rootletin, KIF5B, beta-tubulin, DDAH-2, ATP-synthase and myeloid leukemia factor 2. SCGN functions as a calcium sensor/coincidence detector modulating vesicular exocytosis of neurotransmitters, neuropeptides or hormones. It also serves as a calcium buffer in neurons. Thus, SCGN may be linked to the pathogenesis of neurological diseases such as Alzheimer's, and also acts as a serum marker of neuronal damage, or as a tumor biomarker. SCGN consists of the three globular domains each of which contains a pair of EF-hand motifs. All six EF hand motifs of SCGN in some eukaryotes, including D. rerio, X. laevis, M. domestica, G. gallus, O. anatinus, could potentially bind six calcium ions. In contrast, SCGNs from higher eukaryotes have at least one non-functional EF-hand motif due to the mutation(s) or deletions. For instance, the EF1 loop does not coordinate calcium ion due to the key residue asparagine replaced by lysine in SCGNs of many mammalian species. Moreover, the EF2 loop seems to be competent for calcium-binding in most mammalian SCGNs except for human and chimpanzee orthologs.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21624641 138 FEEFDTDRDGYISHRELGDCMRTLGYMPTEMELLEVSQHIKMR---MG-------GRVDFEEFVELIGPK-------LRE 200
Cdd:cd16178   5 WQHFDADESGYIEGKELDNFFKDLLKKLGTKDTISADEVQDVKecfMSaydvtgdGRIQIQELANIILPDdenfllfFRR 84

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21624641 201 ETAHMLGVRELRIaFREFDRDRDGRITVAELREAVPALL---GEPLAGPELDE----MLREVDLNGDGTVDFDEFVMMLS 273
Cdd:cd16178  85 EEPLDSSVEFMRI-WRKYDADSSGYISAAELKNFLRDLFlqhKKVITEDKLDEytdtMMKIFDKNKDGRLDLNDMARILA 163

The penta-EF hand (PEF) family; The penta-EF hand (PEF) family contains a group of five EF-hand calcium-binding proteins, including several classical calpain large catalytic subunits (CAPN1, 2, 3, 8, 9, 11, 12, 13, 14), two calpain small subunits (CAPNS1 and CAPNS2), as well as non-calpain PEF proteins, ALG-2 (apoptosis-linked gene 2, also termed programmed cell death protein 6, PDCD6), peflin, sorcin, and grancalcin. Based on the sequence similarity of EF1 hand, ALG-2 and peflin have been classified into group I PEF proteins. Calcium-dependent protease calpain subfamily members, sorcin and grancalcin, are group II PEF proteins. Calpains (EC 3.4.22.17) are calcium-activated intracellular cysteine proteases that play important roles in the degradation or functional modulation in a variety of substrates. They have been implicated in a number of physiological processes such as cell cycle progression, remodeling of cytoskeletal-cell membrane attachments, signal transduction, gene expression and apoptosis. ALG-2 is a pro-apoptotic factor that forms a homodimer in the cell or a heterodimer with its closest paralog peflin through their EF5s. Peflin is a 30-kD PEF protein with a longer N-terminal hydrophobic domain than any other member of the PEF family, and it contains nine nonapeptide (A/PPGGPYGGP) repeats. It exists only as a heterodimer with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+. ALG-2 interacts with various proteins in a Ca2+-dependent manner. Sorcin (for soluble resistance-related calcium binding protein) is a soluble resistance-related calcium-binding protein that participates in the regulation of calcium homeostasis in cells. Grancalcin is a cytosolic Ca2+-binding protein specifically expressed in neutrophils and monocytes/macrophages. It plays a key role in leukocyte-specific functions that are responsible for host defense. Grancalcin can form a heterodimer together with sorcin. Members in this family contain five EF-hand motifs attached to an N-terminal region of variable length containing one or more short Gly/Pro-rich sequences. These proteins form homodimers or heterodimers through pairing between the 5th EF-hands from the two molecules. Unlike calmodulin, the PEF domains do not undergo major conformational changes upon binding Ca2+.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21624641 125 ELGPEELDEL-------QAAFEEFDTDRDGYISHRELGDCMRTLGYMPTEmellEVSQHIKMRMG---GRVDFEEFVELi 194
Cdd:cd15897  56 KLNFSEFKGLwnyikawQEIFRTYDTDGSGTIDSNELRQALSGAGYRLSE----QTYDIIIRRYDrgrGNIDFDDFIQC- 130

                        90       100       110
                ....*....|....*....|....*....|....
gi 21624641 195 gpklreetahMLGVRELRIAFREFDRDRDGRITV 228
Cdd:cd15897 131 ----------CVRLQRLTDAFRRYDKDQDGQIQV 154

EF hand; The EF-hands can be divided into two classes: signalling proteins and buffering/transport proteins. The first group is the largest and includes the most well-known members of the family such as calmodulin, troponin C and S100B. These proteins typically undergo a calcium-dependent conformational change which opens a target binding site. The latter group is represented by calbindin D9k and do not undergo calcium dependent conformational changes.

                          10        20
                  ....*....|....*....|....*...
gi 21624641   247 ELDEMLREVDLNGDGTVDFDEFVMMLSR 274
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELLKK 28

EF-hand domain pair;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21624641   132 DELQAAFEEFDTDRDGYISHRELGDCMRTLGymptemellevsqhikmrmggrvdfeefvelIGPKLREEtahmlgvrEL 211
Cdd:pfam13499   2 EKLKEAFKLLDSDGDGYLDVEELKKLLRKLE-------------------------------EGEPLSDE--------EV 42

                          90       100
                  ....*....|....*....|....
gi 21624641   212 RIAFREFDRDRDGRITVAELREAV 235
Cdd:pfam13499  43 EELFKEFDLDKDGRISFEEFLELY 66

EF-hand domain;

                          10        20        30
                  ....*....|....*....|....*....|
gi 21624641   133 ELQAAFEEFDTDRDGYISHRELGDCMRTLG 162
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKALRSLG 30

EF-hand motif found in eukaryotic phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11) isozymes; PI-PLC isozymes are signaling enzymes that hydrolyze the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which goes on to phosphorylate other molecules, leading to altered cellular activity. Calcium is required for the catalysis. This family corresponds to the four EF-hand motifs containing PI-PLC isozymes, including PI-PLC-beta (1-4), -gamma (1-2), -delta (1,3,4), -epsilon (1), -zeta (1), eta (1-2). Lower eukaryotes such as yeast and slime molds contain only delta-type isozymes. In contrast, other types of isoforms present in higher eukaryotes. This family also includes 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase 1 (PLC1) from fungi. Some homologs from plants contain only two atypical EF-hand motifs and they are not included. All PI-PLC isozymes except sperm-specific PI-PLC-zeta share a core set of domains, including an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core, and a single C2 domain. PI-PLC-zeta lacks the PH domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. Most of EF-hand motifs found in PI-PLCs consist of a helix-loop-helix structure, but lack residues critical to metal binding. Moreover, the EF-hand region of most of PI-PLCs may have an important regulatory function, but it has yet to be identified. However, PI-PLC-zeta is a key exception. It is responsible for Ca2+ oscillations in fertilized oocytes and exhibits a high sensitivity to Ca2+ mediated through its EF-hand domain. In addition, PI-PLC-eta2 shows a canonical EF-loop directing Ca2+-sensitivity and thus can amplify transient Ca2+ signals. Also it appears that PI-PLC-delta1 can regulate the binding of PH domain to PIP2 in a Ca2+-dependent manner through its functionally important EF-hand domains. PI-PLCs can be activated by a variety of extracellular ligands, such as growth factors, hormones, cytokines and lipids. Their activation has been implicated in tumorigenesis and/or metastasis linked to migration, proliferation, growth, inflammation, angiogenesis and actin cytoskeleton reorganization. PI-PLC-beta isozymes are activated by G-protein coupled receptor (GPCR) through different mechanisms. However, PI-PLC-gamma isozymes are activated by receptor tyrosine kinase (RTK), such as Rho and Ras GTPases. In contrast, PI-PLC-epsilon are activated by both GPCR and RTK. PI-PLC-delta1 and PLC-eta 1 are activated by GPCR-mediated calcium mobilization. The activation mechanism for PI-PLC-zeta remains unclear.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21624641 134 LQAAFEEFDTDRDGYISHRELGDCMRTLGYMPTEMELLEVSQHIKMRMGGRVDFEEFVELIgpklreetaHMLGVR-ELR 212
Cdd:cd15898   2 LRRQWIKADKDGDGKLSLKEIKKLLKRLNIRVSEKELKKLFKEVDTNGDGTLTFDEFEELY---------KSLTERpELE 72

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 21624641 213 IAFREFDRDRDGRITVAELREAVPALLGEPLAGPELDEMLREVDLNG-DGTVDFDEFV-MMLSRH 275
Cdd:cd15898  73 PIFKKYAGTNRDYMTLEEFIRFLREEQGENVSEEECEELIEKYEPEReNRQLSFEGFTnFLLSPE 137

EF-hand, calcium binding motif, found in apoptosis-linked gene 2 protein (ALG-2) and similar proteins; ALG-2, also termed programmed cell death protein 6 (PDCD6), or probable calcium-binding protein ALG-2, is one of the prototypic members of the penta EF-hand protein family. It is a widely expressed calcium-binding modulator protein associated with cell proliferation and death, as well as cell survival. ALG-2 acts as a pro-apoptotic factor participating in T cell receptor-, Fas-, and glucocorticoid-induced programmed cell death, and also serves as a useful molecular marker for the prognosis of cancers. Moreover, ALG-2 functions as a calcium ion sensor at endoplasmic reticulum (ER) exit sites, and modulates ER-stress-stimulated cell death and neuronal apoptosis during organ formation. Furthermore, ALG-2 can mediate the pro-apoptotic activity of cisplatin or tumor necrosis factor alpha (TNFalpha) through the down-regulation of nuclear factor-kappaB (NF-kappaB) expression. It also inhibits angiogenesis through PI3K/mTOR/p70S6K pathway by interacting of vascular endothelial growth factor receptor-2 (VEGFR-2). In addition, nuclear ALG-2 may participate in the post-transcriptional regulation of Inositol Trisphosphate Receptor Type 1 (IP3R1) pre-mRNA at least in part by interacting with CHERP (Ca2+ homeostasis endoplasmic reticulum protein) calcium-dependently. ALG-2 contains five serially repeated EF-hand motifs and interacts with various proteins, including ALG-2-interacting protein X (Alix), Fas, annexin XI, death-associated protein kinase 1 (DAPk1), Tumor susceptibility gene 101 (TSG101), Sec31A, phospholipid scramblase 3 (PLSCR3), the P-body component PATL1, and endosomal sorting complex required for transport (ESCRT)-III-related protein IST1, in a calcium-dependent manner. It forms a homodimer in the cell or a heterodimer with its closest paralog peflin. Among the PEF proteins, ALG-2 can bind three Ca2+ ions through its EF1, EF3, and EF5 hands, where it is unique in that its EF5 hand binds Ca2+ ion in a canonical coordination.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21624641 133 ELQAAFEEFDTDRDGYISHRELGDCMRTLGYMPTEMELlevsqhIKMRMG-------GRVDFEEFVELIgpKLreetahm 205
Cdd:cd16183   1 FLWNVFQRVDKDRSGQISATELQQALSNGTWTPFNPET------VRLMIGmfdrdnsGTINFQEFAALW--KY------- 65

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 21624641 206 lgVRELRIAFREFDRDRDGRITVAELREAVPAlLGEPLAGPELDEMLREVDLNGDGTVDFDEFV 269
Cdd:cd16183  66 --ITDWQNCFRSFDRDNSGNIDKNELKQALTS-FGYRLSDQFYDILVRKFDRQGRGTIAFDDFI 126

Penta-EF hand, calcium binding motifs, found in calpain-12 (CAPN12); CAPN12, also termed calcium-activated neutral proteinase 12 (CANP 12), is a calpain large subunit mainly expressed in the cortex of the hair follicle. It may affect apoptosis regulation. CAPN12 contains a short N-terminal anchor helix, followed by a calpain cysteine protease (CysPc) domain, a C2-domain-like (C2L) domain, and a C-terminal Ca2+-binding penta-EF-hand (PEF) domain.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21624641 115 LLNRVFGKDRELGPEELDELQAAFEEFDTDRDgyishrelgdcmrtlgymPTEMELLEVSQHIKM---RMGGRVDFEEFV 191
Cdd:cd16194   5 LFQELAGEDEEINASELQKILSIALERAHTSK------------------PREFGLRTCRQLIQCfdhGQNGKLALEEFQ 66

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21624641 192 ELIGpKLREETAhmlgvrelriAFREFDRDRDGRITVAELREAVPAllgeplAGPELDEMLREVDLNGDGT----VDFDE 267
Cdd:cd16194  67 QLWG-YLLEWQA----------IFTKFDEDTSGTMDSYELRLALNA------AGFHLNNQLTETLTSRYRDsrlrVDFES 129

                ....*.
gi 21624641 268 FVMMLS 273
Cdd:cd16194 130 FLSCLA 135

EF-hand, calcium binding motif, found in calretinin (CR); CR, also termed 29 kDa calbindin, is a cytosolic hexa-EF-hand calcium-binding protein predominantly expressed in a variety of normal and tumorigenic t specific neurons of the central and peripheral nervous system. It possibly functions as a calcium buffer, calcium sensor, and apoptosis regulator, which may be implicated in many biological processes, including cell proliferation, differentiation, and cell death. CR contains six EF-hand motifs within two independent domains, CR I-II and CR III-VI. CR I-II consists of EF-hand motifs 1 and 2, and CR III-VI consists of EF-hand motifs 3-6. The first 5 EF-hand motifs are capable of binding calcium ions, while the EF-hand 6 is inactive. Thus, CR has two pairs of cooperative binding sites (I-II and III-IV), which display high affinity calcium-binding sites, and one independent calcium ion-binding site (V), which displays lower affinity binding.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21624641 138 FEEFDTDRDGYISHRELGDCMRTL-------GYMPT----EMELLEVSQHIKMRMGGRVDFEEFVELigpkLREETAHML 206
Cdd:cd16177   5 WKHFDADGNGYIEGKELENFFRELerarrgaGVDSKsanfGEKMKEFMQKYDKNADGRIEMAELAQI----LPTEENFLL 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21624641 207 GVR-------ELRIAFREFDRDRDGRITVAELREAVPALL---GEPLAGPELDE----MLREVDLNGDGTVDFDEFVMML 272
Cdd:cd16177  81 CFRqhvgsssEFMEAWRKYDTDRSGYIEANELKGFLSDLLkkaNRPYDEKKLQEytqtILRMFDLNGDGKLGLSEMARLL 160

EF-hand, calcium binding motif, found in CREC-EF hand family; The CREC (Cab45/reticulocalbin/ERC45/calumenin)-EF hand family contains a group of six EF-hand, low-affinity Ca2+-binding proteins, including reticulocalbin (RCN-1), ER Ca2+-binding protein of 55 kDa (ERC-55, also known as TCBP-49 or E6BP), reticulocalbin-3 (RCN-3), Ca2+-binding protein of 45 kDa (Cab45 and its splice variant Cab45b), and calumenin ( also known as crocalbin or CBP-50). The proteins are not only localized in various parts of the secretory pathway, but also found in the cytosolic compartment and at the cell surface. They interact with different ligands or proteins and have been implicated in the secretory process, chaperone activity, signal transduction as well as in a large variety of disease processes.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21624641 105 HDAAQRTYGPLLNRV-FGKDRELGPEEL-------------DELQAAFEEFDTDRDGYISHRELGDCMrtlgymptemel 170
Cdd:cd15899  30 PEESKRRLGVIVSKMdVDKDGFISAKELhswilesfkrhamEESKEQFRAVDPDEDGHVSWDEYKNDT------------ 97

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21624641 171 levsqhikmrMGGRVDFEEFVELiGPKLREETAHMLGVRELRiaFREFDRDRDGRITVAELR-----EAVPALLGEPLAg 245
Cdd:cd15899  98 ----------YGSVGDDEENVAD-NIKEDEEYKKLLLKDKKR--FEAADQDGDLILTLEEFLaflhpEESPYMLDFVIK- 163

                       170       180
                ....*....|....*....|....
gi 21624641 246 peldEMLREVDLNGDGTVDFDEFV 269
Cdd:cd15899 164 ----ETLEDLDKNGDGFISLEEFI 183

EF hand; The EF-hands can be divided into two classes: signalling proteins and buffering/transport proteins. The first group is the largest and includes the most well-known members of the family such as calmodulin, troponin C and S100B. These proteins typically undergo a calcium-dependent conformational change which opens a target binding site. The latter group is represented by calbindin D9k and do not undergo calcium dependent conformational changes.

                          10        20
                  ....*....|....*....|....*.
gi 21624641   210 ELRIAFREFDRDRDGRITVAELREAV 235
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELL 26

EF-hand, calcium binding motif, found in Drosophila melanogaster calbindin-32 (CBN) and similar proteins; CBN, the product of the cbn gene, is a Drosophila homolog to vertebrate neuronal six EF-hand calcium binding proteins. It is expressed through most of ontogenesis with a selective distribution in the nervous system and in a few small adult thoracic muscles. Its precise biological role remains unclear. CBN contains six EF-hand motifs, but some of them may not bind calcium ions due to the lack of key residues.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21624641 133 ELQAAFEEFDTDRDGYISHRELGDCMRTL------GYMPTEMELLEVSQHI----KMRMGGRVDFEEFVELIgpKLRE-- 200
Cdd:cd16179  96 EFMKVWREYDKDNSGYIEADELKNFLKHLlkeakrDNDVSEDKLIEYTDTIlqlfDRNKDGKLQLSEMARLL--PVKEnf 173

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21624641 201 ------ETAHMLGVRELRIAFREFDRDRDGRITVAELREAVPALL---GEPLAGPELDEM----LREVDLNGDGTVDFDE 267
Cdd:cd16179 174 lcrpifKGAGKLTREDIDRVFALYDRDNNGTIENEELTGFLKDLLelvQEDYDEQDLEEFkeiiLRGWDFNNDGKISRKE 253

                ....*
gi 21624641 268 FVMML 272
Cdd:cd16179 254 LTMLL 258

EF-hand domain;

                          10        20
                  ....*....|....*....|....*.
gi 21624641   210 ELRIAFREFDRDRDGRITVAELREAV 235
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKAL 26

Penta-EF hand, calcium binding motifs, found in Drosophila melanogaster calpain-A (CalpA), calpain-B (CalpB), and similar proteins; The family contains two calpains that have been found in Drosophila, CalpA and CalpB. CalpA, also termed calcium-activated neutral proteinase A (CANP A), or calpain-A catalytic subunit, is a Drosophila calpain homolog specifically expressed in a few neurons in the central nervous system, in scattered endocrine cells in the midgut, and in blood cells. CalpB, also termed calcium-activated neutral proteinase B (CANP B), contains calpain-B catalytic subunit 1 and calpain-B catalytic subunit 2. Both CalpA and CalpB are closely related to that of vertebrate calpains, and they share similar domain architecture, which consists of four domains: the N-terminal domain I, the catalytic domain II carrying the three active site residues, Cys, His and Asn, the Ca2+-regulated phospholipid-binding domain III, and penta-EF-hand Ca2+-binding domain IV. Besides, CalpA and CalpB display some distinguishing structural features that are not found in mammalian typical calpains. CalpA harbors a 76 amino acid long hydrophobic stretch inserted in domain IV, which may be involved in membrane attachment of this enzyme. CalpB has an unusually long N-terminal tail of 224 amino acids, which belongs to the class of intrinsically unstructured proteins (IUP) and may become ordered upon binding to target protein(s). Moreover, they do not need small regulatory subunits for their catalytic activity, and their proteolytic function is not regulated by an intrinsic inhibitor as the Drosophila genome contains neither regulatory subunit nor calpastatin orthologs. As a result, they may exist as a monomer or perhaps as a homo- or heterodimer together with a second large subunit. Furthermore, both CalpA and CalpB are dispensable for viability and fertility and do not share vital functions during Drosophila development. Phosphatidylinositol 4,5-diphosphate, phosphatidylinositol 4-monophosphate, phosphatidylinositol, and phosphatidic acid can stimulate the activity and the rate of activation of CalpA, but not CalpB. Calpain A modulates Toll responses by limited Cactus/IkappaB proteolysis. CalpB directly interacts with talin, an important component of the focal adhesion complex, and functions as an important modulator in border cell migration within egg chambers, which may act via the digestion of talin. CalpB can be phosphorylated by cAMP-dependent protein kinase (protein kinase A, PKA; EC 2.7.11.11) at Ser240 and Ser845, as well as by mitogen-activated protein kinase (ERK1 and ERK2; EC 2.7.11.24) at Thr747. The activation of the ERK pathway by extracellular signals results in the phosphorylation and activation of calpain B. In Schneider cells (S2), calpain B was mainly in the cytoplasm and upon a rise in Ca2+ the enzyme adhered to intracellular membranes.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21624641 177 IKMR---MGGRVDFEEFVELIGpklreetahmlgvrELRI---AFREFDRDRDGRITVAELREAVPAllgeplAGPELDE 250
Cdd:cd16196  47 VAMMdvdRSGKLGFEEFKKLWE--------------DLRSwkrVFKLFDTDGSGSFSSFELRNALNS------AGFRLSN 106

                        90       100       110
                ....*....|....*....|....*....|
gi 21624641 251 ------MLREVdlNGDGTVDFDEFVMMLSR 274
Cdd:cd16196 107 atlnalVLRYS--NKDGRISFDDFIMCAVK 134

Penta-EF hand, calcium binding motifs, found in Drosophila melanogaster calpain-A (CalpA), calpain-B (CalpB), and similar proteins; The family contains two calpains that have been found in Drosophila, CalpA and CalpB. CalpA, also termed calcium-activated neutral proteinase A (CANP A), or calpain-A catalytic subunit, is a Drosophila calpain homolog specifically expressed in a few neurons in the central nervous system, in scattered endocrine cells in the midgut, and in blood cells. CalpB, also termed calcium-activated neutral proteinase B (CANP B), contains calpain-B catalytic subunit 1 and calpain-B catalytic subunit 2. Both CalpA and CalpB are closely related to that of vertebrate calpains, and they share similar domain architecture, which consists of four domains: the N-terminal domain I, the catalytic domain II carrying the three active site residues, Cys, His and Asn, the Ca2+-regulated phospholipid-binding domain III, and penta-EF-hand Ca2+-binding domain IV. Besides, CalpA and CalpB display some distinguishing structural features that are not found in mammalian typical calpains. CalpA harbors a 76 amino acid long hydrophobic stretch inserted in domain IV, which may be involved in membrane attachment of this enzyme. CalpB has an unusually long N-terminal tail of 224 amino acids, which belongs to the class of intrinsically unstructured proteins (IUP) and may become ordered upon binding to target protein(s). Moreover, they do not need small regulatory subunits for their catalytic activity, and their proteolytic function is not regulated by an intrinsic inhibitor as the Drosophila genome contains neither regulatory subunit nor calpastatin orthologs. As a result, they may exist as a monomer or perhaps as a homo- or heterodimer together with a second large subunit. Furthermore, both CalpA and CalpB are dispensable for viability and fertility and do not share vital functions during Drosophila development. Phosphatidylinositol 4,5-diphosphate, phosphatidylinositol 4-monophosphate, phosphatidylinositol, and phosphatidic acid can stimulate the activity and the rate of activation of CalpA, but not CalpB. Calpain A modulates Toll responses by limited Cactus/IkappaB proteolysis. CalpB directly interacts with talin, an important component of the focal adhesion complex, and functions as an important modulator in border cell migration within egg chambers, which may act via the digestion of talin. CalpB can be phosphorylated by cAMP-dependent protein kinase (protein kinase A, PKA; EC 2.7.11.11) at Ser240 and Ser845, as well as by mitogen-activated protein kinase (ERK1 and ERK2; EC 2.7.11.24) at Thr747. The activation of the ERK pathway by extracellular signals results in the phosphorylation and activation of calpain B. In Schneider cells (S2), calpain B was mainly in the cytoplasm and upon a rise in Ca2+ the enzyme adhered to intracellular membranes.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21624641 126 LGPEELDEL-------QAAFEEFDTDRDGYISHRELGDCMRTLGYmptemellEVSQHIK----MRMG---GRVDFEEFV 191
Cdd:cd16196  58 LGFEEFKKLwedlrswKRVFKLFDTDGSGSFSSFELRNALNSAGF--------RLSNATLnalvLRYSnkdGRISFDDFI 129

                        90       100       110
                ....*....|....*....|....*....|....*....
gi 21624641 192 eligpklreetahMLGVReLRIA---FREFDRDRDGRIT 227
Cdd:cd16196 130 -------------MCAVK-LKTMfeiFKEKDPRGGGRAT 154

N-terminal domain of Myosin essential light chain ELC; ELC is part of the apicomplexan membrane-associated protein complex called the glideosome, which is essential for parasite motility. The glideosome is composed of six proteins: myosin A (MyoA), essential light chain ELC, myosin light chain MLC1 (also called MTIP), and the glideosome-associated proteins GAP40, GAP45, and GAP50. MyoA is a Class XIV myosin implicated in gliding motility, as well as host cell and tissue invasion by parasites. ELC binds to the MyoA neck region adjacent to the MLC1-binding site, and both myosin light chains co-located to the glideosome. Although ELCs bind to a conserved MyoA sequence, P. falciparum ELC adopts a distinct structure in the free and MyoA-bound state. Therefore ELCs enhance MyoA performance by inducing alpha helical structure formation in MyoA and thus stiffening its lever arm. It has been shown that disruption of MyoA, MLC1, or ELC have dramatic effects on parasite motility but do not affect parasite shape or replication. The ELC N-terminal domain is part of the EF-hand calcium binding motif superfamily. Calcium binding has no effect on the structure of ELCs.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 21624641 132 DELQAAFEEFDTDRDGYISHRELGDCMRTLGYMPTEMELLEVSQHIKMRmggrvDFEEFV 191
Cdd:cd22949   3 EKFREAFILFDRDGDGELTMYEAVLAMRSCGIPLTNDEKDALPASMNWD-----QFENWA 57

EF-hand, calcium binding motif, found in parvalbumin-like EF-hand family; The family includes alpha- and beta-parvalbumins, and a group of uncharacterized calglandulin-like proteins. Parvalbumins are small, acidic, cytosolic EF-hand-containing Ca2+-buffer and Ca2+ transporter/shuttle proteins belonging to EF-hand superfamily. They are expressed by vertebrates in fast-twitch muscle cells, specific neurons of the central and peripheral nervous system, sensory cells of the mammalian auditory organ (Corti's cell), and some other cells, and characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. Thus, they may play an additional role in Mg2+ handling. Moreover, parvalbumins represent one of the major animal allergens. In metal-bound states, parvalbumins possess a rigid and stable tertiary structure and display strong allergenicity. In contrast, the metal-free parvalbumins are intrinsically disordered, and the loss of metal ions results in a conformational change that decreases their IgE binding capacity. Furthermore, parvalbumins have been widely used as a neuronal marker for a variety of functional brain systems. They also function as a Ca2+ shuttle transporting Ca2+ from troponin-C (TnC) to the sarcoplasmic reticulum (SR) Ca2+ pump during muscle relaxation. Thus they may facilitate myocardial relaxation and play important roles in cardiac diastolic dysfunction. Parvalbumins consists of alpha- and beta- sublineages, which can be distinguished on the basis of isoelectric point (pI > 5 for alpha; pI

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21624641 179 MRMGGRVDFEEFVELIGPKLREETahmlgvrELRIAFREFDRDRDGRITVAELREAvpaLLGEPLAGPELDE-----MLR 253
Cdd:cd16251  11 FRAHGSFNYKKFFEHVGLKQKSED-------QIKKVFQILDKDKSGFIEEEELKYI---LKGFSIAGRDLTDeetkaLLA 80

                        90
                ....*....|....*...
gi 21624641 254 EVDLNGDGTVDFDEFVMM 271
Cdd:cd16251  81 AGDTDGDGKIGVEEFATL 98

N-terminal domain of Kruppel-like factor 14; Kruppel-like factor 14 (KLF14; also known as Krueppel-like factor 14 or basic transcription element-binding protein 5/BTEB5) is a protein that in humans is encoded by the KLF14 gene. KLF14 regulates the transcription of various genes, including TGFbetaRII (the type II receptor for TGFbeta). KLF14 is expressed in many tissues, lacks introns, and is subject to parent-specific expression. It also appears to be a master regulator of gene expression in adipose tissue. KLF14 is associated with coronary artery disease, hypercholesterolemia, and type 2 diabetes. KLF9, KLF10, KLF11, KLF13, KLF14, and KLF16 share a conserved alpha-helical motif AA/VXXL that mediates their binding to Sin3A and their activities as transcriptional repressors. KLF14 belongs to a family of proteins, called the Specificity Protein (SP)/KLF family, characterized by a C-terminal DNA-binding domain of 81 amino acids consisting of three Kruppel-like C2H2 zinc fingers. These factors bind to a loose consensus motif, namely NNRCRCCYY (where N is any nucleotide; R is A/G, and Y is C/T), such as the recurring motifs in GC and GT boxes (5'-GGGGCGGGG-3' and 5-GGTGTGGGG-3') that are present in promoters and more distal regulatory elements of mammalian genes. Members of the KLF family can act as activators or repressors of transcription depending on cell and promoter context. KLFs regulate various cellular functions, such as proliferation, differentiation, and apoptosis, as well as the development and homeostasis of several types of tissue. In addition to the C-terminal DNA-binding domain, each KLF also has a unique N-terminal activation/repression domain that confers specificity and allows it to bind specifically to a certain partner, leading to distinct activities in vivo. This model represents the N-terminal domain of KLF14.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 21624641  56 GSSGEQTGPEAPGSSNNPPSTGEGPAGAPPASPGPASSrQSHRHRP 101
Cdd:cd21576 142 SSFGAPAIPSAPAAPGAPAVSGEVPGGAPGAGPAPAAG-PAPRRRP 186