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 18031827  89 KLKWYFKLFDQDGNGKIDRDEMETIFKAIqditrsYEIPPDDIVSLIYERIDVNNEGELTLEEFITGAK 157
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKSL------GEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18031827   62 DMDGDGYIDFVEYIAAVSLLLK-GEINQKLKWYFKLFDQDGNGKIDRDEMETIfkaiqdITRSYEIPPDDIVSLIYERID 140
Cdd:PTZ00184  57 DADGNGTIDFPEFLTLMARKMKdTDSEEEIKEAFKVFDRDGNGFISAAELRHV------MTNLGEKLTDEEVDEMIREAD 130

                         90
                 ....*....|...
gi 18031827  141 VNNEGELTLEEFI 153
Cdd:PTZ00184 131 VDGDGQINYEEFV 143

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 18031827  89 KLKWYFKLFDQDGNGKIDRDEMETIFKAIqditrsYEIPPDDIVSLIYERIDVNNEGELTLEEFITGAK 157
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKSL------GEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

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 18031827  29 SGLITLFELKNMLEMQGMTeeaSSY--VDQVFFTFDMDGDGYIDFVEYIAAVSLLlkgeinQKLKWYFKLFDQDGNGKID 106
Cdd:cd16185  14 SGSIDVNELQKALAGGGLL---FSLatAEKLIRMFDRDGNGTIDFEEFAALHQFL------SNMQNGFEQRDTSRSGRLD 84

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 18031827 107 RDEmetIFKAIqdITRSYEIPPdDIVSLIYERIDVNNEGELTLEEFI 153
Cdd:cd16185  85 ANE---VHEAL--AASGFQLDP-PAFQALFRKFDPDRGGSLGFDDYI 125

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18031827  88 QKLKWYFKLFDQDGNGKIDRDEMETIFKAIQDitrsyeippddivsLIYERIDVNNEGELTLEEFITG--AKEHPDIMEM 165
Cdd:COG5126   5 RKLDRRFDLLDADGDGVLERDDFEALFRRLWA--------------TLFSEADTDGDGRISREEFVAGmeSLFEATVEPF 70

                ....*..
gi 18031827 166 LTKMMDL 172
Cdd:COG5126  71 ARAAFDL 77

serine/threonine protein phosphatase 2A regulatory subunit B" subunit gamma; Heterotrimeric serine/threonine protein phosphatase 2A (PP2A) consists of scaffolding (A), catalytic (C), and variable (B, B', and B") subunits. The variable subunits dictate subcellular localization and substrate specificity of the PP2A holoenzyme. This subfamily includes protein phosphatase subunit G5PR (also known as serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma, G4-1, G5pr, GDRM, SPGF36, or C14orf10) that is encoded by the PPP2R3C gene. It is involved in the control of the dynamic organization of the cortical cytoskeleton and plays an important role in the organization of interphase microtubule arrays in part through the regulation of nucleation geometry. G5PR is involved in the ontogeny of multiple organs, especially critical for testis development and spermatogenesis. PPP2R3C gene variants cause syndromic 46,XY gonadal dysgenesis and impaired spermatogenesis in humans, and thus is emerging as a potential therapeutic target for male infertility.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18031827  53 YVDQVF---FTFD--MDGDGYIDFV---EYiaavslllKGEInQKLKWYFKLFDQDGNGKIDRDEMETIFKAIQDITRSY 124
Cdd:cd21505 255 FIDRVFqecLTYNgeMDYKTFLDFVlamEN--------RKEP-QALQYFFRILDLKGQGYLTPFTLNYFFRAIQEKMKEH 325

                        90       100       110
                ....*....|....*....|....*....|..
gi 18031827 125 EIPP---DDIVSLIYERIDVNNEGELTLEEFI 153
Cdd:cd21505 326 GQEPvsfEDVKDEIFDMVKPKDPLKITLQDLI 357

EF-hand, extracellular calcium-binding (EC) motif, found in secreted modular calcium-binding protein 2 (SMOC-2); SMOC-2, also termed SPARC-related modular calcium-binding protein 2, or smooth muscle-associated protein 2 (SMAP-2), is a ubiquitously expressed matricellular protein that enhances the response to angiogenic growth factors, mediate cell adhesion, keratinocyte migration, and metastasis. It is also associated with vitiligo and craniofacial and dental defects. Moreover, SMOC-2 acts as an Arf1 GTPase-activating protein (GAP) that interacts with clathrin heavy chain (CHC) and clathrin assembly protein CALM and functions in the retrograde, early endosome/trans-Golgi network (TGN) pathway in a clathrin- and AP-1-dependent manner. It also contributes to mitogenesis via activation of integrin-linked kinase (ILK). SMOC-2 contains a follistatin-like (FS) domain, two thyroglobulin-like (TY) domains, a novel domain, which is found only in the homologous SMOC-1, and an extracellular calcium-binding (EC) domain with two EF-hand calcium-binding motifs.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 18031827  92 WYFKLFDQDGNGKIDRDEMETIFKAIQDITRsyeipPDDIVSLIYERIDVNNEGELTLEEFI 153
Cdd:cd16241  51 WYFKQLDKNSSGDIGKKEIKPFKRFLRKKSK-----PKKCVKKFVEYCDVNNDKSLSVQELM 107

Eps15 homology domain; found in proteins implicated in endocytosis, vesicle transport, and signal transduction. The alignment contains a pair of EF-hand motifs, typically one of them is canonical and binds to Ca2+, while the other may not bind to Ca2+. A hydrophobic binding pocket is formed by residues from both EF-hand motifs. The EH domain binds to proteins containing NPF (class I), [WF]W or SWG (class II), or H[TS]F (class III) sequence motifs.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 18031827  93 YFKLFDQDGNGKIDRDEMETIFKAIQditrsyeiPPDDIVSLIYERIDVNNEGELTLEEFITG 155
Cdd:cd00052   4 IFRSLDPDGDGLISGDEARPFLGKSG--------LPRSVLAQIWDLADTDKDGKLDKEEFAIA 58

EF-hand, extracellular calcium-binding (EC) motif, found in secreted protein acidic and rich in cysteine (SPARC)-like proteins; The SPARC protein family represents a diverse group of proteins that share a follistatin-like (FS) domain and an extracellular calcium-binding (EC) domain with two EF-hand motifs. It includes SPARC (for secreted protein acidic and rich in cysteine, also termed osteonectin/ON, or basement-membrane protein 40/BM-40), SPARC-like protein 1 (for secreted protein, acidic and rich in cysteines-like 1/ SPARCL1, also termed high endothelial venule protein/Hevi, or MAST 9, or SC-1, or RAGS-1, or QR1, or ECM 2), testicans 1, 2, and 3 (also termed SPARC/osteonectin, CWCV, and Kazal-like domains proteoglycans, or SPOCK), secreted modular calcium-binding protein SMOC-1 (also termed SPARC-related modular calcium-binding protein 1) and SMOC-2 (also termed SPARC-related modular calcium-binding protein 2, or smooth muscle-associated protein 2/SMAP-2), follistatin-related protein 1 (FRP-1, also termed follistatin-like protein 1/fstl-1, TSC-36/Flik, TGF-beta inducible protein). The SPARC proteins have been implicated in modulating cell interaction with the extracellular milieu, including regulation of extracellular matrix assembly and deposition, counter-adhesion, effects on extracellular protease activity, and modulation of growth factor/cytokine signaling pathways, as well as in development and disease.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 18031827  90 LKWYFKLFDQDGNGKIDRDEMETIfkaiqditRSYEIPPDDIVSLIYERIDVNNEGELTLEEFI 153
Cdd:cd00252  47 AQWEFDNLDNNKDGKLDKRELAPF--------RAPLMPLEHCARGFFESCDLNKDKKISLQEWL 102

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 18031827     89 KLKWYFKLFDQDGNGKIDRDEMETIFKAI 117
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

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 18031827  53 YVDQVFFTFDMDGDGYIDFVEYIAAVSLLLKGEINQKLKWYFKLFDQDGNGKIDRDEMETIFKAIQditrsyeIPPDdiV 132
Cdd:cd15898   1 WLRRQWIKADKDGDGKLSLKEIKKLLKRLNIRVSEKELKKLFKEVDTNGDGTLTFDEFEELYKSLT-------ERPE--L 71

                        90       100
                ....*....|....*....|..
gi 18031827 133 SLIYERIDVNNEGELTLEEFIT 154
Cdd:cd15898  72 EPIFKKYAGTNRDYMTLEEFIR 93

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 18031827    89 KLKWYFKLFDQDGNGKIDRDEMETIFKAI 117
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELLKKL 29

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 18031827  35 FELKNMLEMQGMTEEASSYVDQVFFTFDMDGDGYIDFVEyiaaVSLLLKG-------EINQKLKWYFKLFDQDGNGKIDR 107
Cdd:cd16251  17 FNYKKFFEHVGLKQKSEDQIKKVFQILDKDKSGFIEEEE----LKYILKGfsiagrdLTDEETKALLAAGDTDGDGKIGV 92

                ....*....
gi 18031827 108 DEMETIFKA 116
Cdd:cd16251  93 EEFATLVAG 101

EF-hand, calcium binding motif, found in mitochondrial calcium uptake proteins MICU1, MICU2, MICU3, and similar proteins; This family includes mitochondrial calcium uptake protein MICU1 and its two additional paralogs, MICU2 and MICU3. MICU1 localizes to the inner mitochondrial membrane (IMM). It functions as a gatekeeper of the mitochondrial calcium uniporter (MCU) and regulates MCU-mediated mitochondrial Ca2+ uptake, which is essential for maintaining mitochondrial homoeostasis. MICU1 and MICU2 are physically associated within the uniporter complex and are co-expressed across all tissues. They may play non-redundant roles in the regulation of the mitochondrial calcium uniporter. At present, the precise molecular function of MICU2 and MICU3 remain unclear. MICU2 may play possible roles in Ca2+ sensing and regulation of MCU, calcium buffering with a secondary impact on transport or assembly and stabilization of MCU. MICU3 likely has a role in mitochondrial calcium handling. All members in this family contains an N-terminal mitochondrial targeting sequence (MTS) as well as two evolutionarily conserved canonical Ca2+-binding EF-hands separated by a long stretch of residues predicted to form alpha-helices.

                        10        20
                ....*....|....*....|....*
gi 18031827  94 FKLFDQDGNGKIDRDEMETIFKAIQ 118
Cdd:cd15900   6 FKMFDLDGDGELDKEEFNKVQSIIR 30

EF-hand, calcium binding motif, found in beta-parvalbumin; Beta-parvalbumin, also termed Oncomodulin-1 (OM), is a small calcium-binding protein that is expressed in hepatomas, as well as in the blastocyst and the cytotrophoblasts of the placenta. It is also found to be expressed in the cochlear outer hair cells of the organ of Corti and frequently expressed in neoplasms. Mammalian beta-parvalbumin is secreted by activated macrophages and neutrophils. It may function as a tissue-specific Ca2+-dependent regulatory protein, and may also serve as a specialized cytosolic Ca2+ buffer. Beta-parvalbumin acts as a potent growth-promoting signal between the innate immune system and neurons in vivo. It has high and specific affinity for its receptor on retinal ganglion cells (RGC) and functions as the principal mediator of optic nerve regeneration. It exerts its effects in a cyclic adenosine monophosphate (cAMP)-dependent manner and can further elevate intracellular cAMP levels. Moreover, beta-parvalbumin is associated with efferent function and outer hair cell electromotility, and can identify different hair cell types in the mammalian inner ear. Beta-parvalbumin is 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+. The EF site displays a high-affinity for Ca2+/Mg2+, and the CD site is a low-affinity Ca2+-specific site. In addition, beta-parvalbumin is distinguished from other parvalbumins by its unusually low isoelectric point (pI = 3.1) and sequence eccentricities (e.g., Y57-L58-D59 instead of F57-I58-E59).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18031827  35 FELKNMLEMQGMTEEASSYVDQVFFTFDMDGDGYIDFVE-------YIAAVSLLLKGEInqklKWYFKLFDQDGNGKIDR 107
Cdd:cd16255  17 FNFKKFFATSGLSKKSADDVKKVFEIIDQDKSGFIEEEElklflqnFSSGARELTDAET----KAFLKAGDSDGDGKIGV 92

                ....*....
gi 18031827 108 DEMETIFKA 116
Cdd:cd16255  93 EEFQALVKA 101

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 18031827  60 TFDMDGDGYIDFVEYIAAVSLLLKGEINQKLKWYFK-LFDQDGNGKIDRDEMetifkaiqditRSYEIP-----PDDIVS 133
Cdd:cd16227 167 DKDKDNDGFISFQEFLGDRAGHEDKEWLLVEKDRFDeDYDKDGDGKLDGEEI-----------LSWLVPdneeiAEEEVD 235

                        90       100
                ....*....|....*....|
gi 18031827 134 LIYERIDVNNEGELTLEEFI 153
Cdd:cd16227 236 HLFASADDDHDDRLSFDEIL 255

EF-hand, calcium binding motif, found in alpha-parvalbumin; Alpha-parvalbumin is cytosolic Ca2+/Mg2+-binding protein expressed mainly in fast-twitch skeletal myofibrils, where it may act as a soluble relaxing factor facilitating the Ca2+-mediated relaxation phase. It is also expressed in rapidly firing neurons, particularly GABA-ergic neurons, and thus may confer protection against Ca2+ toxicity. The major role of alpha-parvalbumin is metal buffering and transport of Ca2+. It binds different metal cations, and exhibits very high affinity for Ca2+ and physiologically significant affinity for Mg2+. Alpha-parvalbumin is 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+. Both metal ion-binding sites in alpha-parvalbumin are high-affinity sites. Additionally, in contrast to beta-parvalbumin, alpha-parvalbumin is less acidic and has an additional residue in the C-terminal helix.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18031827  35 FELKNMLEMQGMTEEASSYVDQVFFTFDMDGDGYIDFVEyiaaVSLLLKG------EINQK-LKWYFKLFDQDGNGKIDR 107
Cdd:cd16254  17 FDYKKFFEMVGLKKKSADDVKKVFHILDKDKSGFIEEDE----LKFVLKGfspdgrDLSDKeTKALLAAGDKDGDGKIGI 92

                ....*.
gi 18031827 108 DEMETI 113
Cdd:cd16254  93 DEFATL 98