calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157743275  74 NISVEELDEIREAFRVLDRDGNGFISKQELGMAMRSLGYMPSEVELAIIMQRLDMDGDGQVDFDEFMTILGPKLvssegR 153
Cdd:PTZ00184   4 QLTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLMARKM-----K 78

                         90       100       110
                 ....*....|....*....|....*....|....
gi 157743275 154 DGFLGNTIDSIFWQFDMQ---RITLEELKHILYH 184
Cdd:PTZ00184  79 DTDSEEEIKEAFKVFDRDgngFISAAELRHVMTN 112

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157743275  74 NISVEELDEIREAFRVLDRDGNGFISKQELGMAMRSLGYMPSEVELAIIMQRLDMDGDGQVDFDEFMTILGPKLvssegR 153
Cdd:PTZ00184   4 QLTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLMARKM-----K 78

                         90       100       110
                 ....*....|....*....|....*....|....
gi 157743275 154 DGFLGNTIDSIFWQFDMQ---RITLEELKHILYH 184
Cdd:PTZ00184  79 DTDSEEEIKEAFKVFDRDgngFISAAELRHVMTN 112

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 157743275   81 DEIREAFRVLDRDGNGFISKQELGMAMRSLGYM--PSEVELAIIMQRLDMDGDGQVDFDEFMTIL 143
Cdd:pfam13499   2 EKLKEAFKLLDSDGDGYLDVEELKKLLRKLEEGepLSDEEVEELFKEFDLDKDGRISFEEFLELY 66

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 157743275    82 EIREAFRVLDRDGNGFISKQELGMAMRSL 110
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157743275  62 SLSAGSDSEQLAnisvEELdeireaFRVLDRDGNGFISKQELGMAMRSLGYMPSEVELAIIMQRLDMDGDGQVDFDEFMT 141
Cdd:NF041410  18 SSTSSARSQQFQ----KQL------FAKLDSDGDGSVSQDELSSALSSKSDDGSLIDLSELFSDLDSDGDGSLSSDELAA 87

                 ....
gi 157743275 142 ILGP 145
Cdd:NF041410  88 AAPP 91

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157743275  74 NISVEELDEIREAFRVLDRDGNGFISKQELGMAMRSLGYMPSEVELAIIMQRLDMDGDGQVDFDEFMTILGPKLvssegR 153
Cdd:PTZ00184   4 QLTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLMARKM-----K 78

                         90       100       110
                 ....*....|....*....|....*....|....
gi 157743275 154 DGFLGNTIDSIFWQFDMQ---RITLEELKHILYH 184
Cdd:PTZ00184  79 DTDSEEEIKEAFKVFDRDgngFISAAELRHVMTN 112

centrin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157743275  78 EELDEIREAFRVLDRDGNGFISKQELGMAMRSLGYMPSEVELAIIMQRLDMDGDGQVDFDEFMTILGPKLVSSEGRDGfl 157
Cdd:PTZ00183  14 DQKKEIREAFDLFDTDGSGTIDPKELKVAMRSLGFEPKKEEIKQMIADVDKDGSGKIDFEEFLDIMTKKLGERDPREE-- 91

                         90       100
                 ....*....|....*....|....*..
gi 157743275 158 gntIDSIFWQFD---MQRITLEELKHI 181
Cdd:PTZ00183  92 ---ILKAFRLFDddkTGKISLKNLKRV 115

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 157743275   81 DEIREAFRVLDRDGNGFISKQELGMAMRSLGYM--PSEVELAIIMQRLDMDGDGQVDFDEFMTIL 143
Cdd:pfam13499   2 EKLKEAFKLLDSDGDGYLDVEELKKLLRKLEEGepLSDEEVEELFKEFDLDKDGRISFEEFLELY 66

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 157743275  81 DEIREAFRVLDRDGNGFISKQELGMAMRSL---GYMPSEVELAIIMQRLDMDGDGQVDFDEFMTI 142
Cdd:cd16251   34 DQIKKVFQILDKDKSGFIEEEELKYILKGFsiaGRDLTDEETKALLAAGDTDGDGKIGVEEFATL 98

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 157743275  68 DSEQLANISVEE-------LDEIREAFRVLDRDGNGFISKQELGMAMRSLGYMPSEVELAIIMQRLDMDGDGQVDFDEFM 140
Cdd:cd16180   47 DRDRSGTINFDEfvglwkyIQDWRRLFRRFDRDRSGSIDFNELQNALSSFGYRLSPQFVQLLVRKFDRRRRGSISFDDFV 126

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 157743275  61 RSLSAGSDSEQLANISVEELDEI-------REAFRVLDRDGNGFISKQELGMAMRSLGYMPSEVELAIIMQRLDmDGDGQ 133
Cdd:cd15897   43 RSMIAMMDRDHSGKLNFSEFKGLwnyikawQEIFRTYDTDGSGTIDSNELRQALSGAGYRLSEQTYDIIIRRYD-RGRGN 121

                 ....*..
gi 157743275 134 VDFDEFM 140
Cdd:cd15897  122 IDFDDFI 128

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 157743275  81 DEIREAFRVLDRDGNGFISKQELGMAM-------RSLgympSEVELAIIMQRLDMDGDGQVDFDEFMtilgpKLVSS 150
Cdd:cd16255   34 DDVKKVFEIIDQDKSGFIEEEELKLFLqnfssgaREL----TDAETKAFLKAGDSDGDGKIGVEEFQ-----ALVKA 101

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 157743275  71 QLANISVEELDEIREAFRVLDRDGNGFISKQELGMAMRslGYMP-----SEVELAIIMQRLDMDGDGQVDFDEFMTIL 143
Cdd:cd16254   24 EMVGLKKKSADDVKKVFHILDKDKSGFIEEDELKFVLK--GFSPdgrdlSDKETKALLAAGDKDGDGKIGIDEFATLV 99

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157743275  78 EELDEIREAFRVLDRDGNGFISKQEL-GMAMRSLGYMPSEvelaiimqrLDMDGDGQVDFDEFMTILGPklvsseGRDGF 156
Cdd:COG5126    2 LQRRKLDRRFDLLDADGDGVLERDDFeALFRRLWATLFSE---------ADTDGDGRISREEFVAGMES------LFEAT 66

                         90       100
                 ....*....|....*....|....*....
gi 157743275 157 LGNTIDSIFWQFDM---QRITLEELKHIL 182
Cdd:COG5126   67 VEPFARAAFDLLDTdgdGKISADEFRRLL 95

EF-hand domain;

                          10        20        30
                  ....*....|....*....|....*....|
gi 157743275   82 EIREAFRVLDRDGNGFISKQELGMAMRSLG 111
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKALRSLG 30

Penta-EF hand, calcium binding motifs, found in sorcin, grancalcin, and similar proteins; The family corresponds to the second group of penta-EF hand (PEF) proteins that includes sorcin, grancalcin, and similar proteins. Sorcin, also termed 22 kDa Ca2+-binding protein, CP-22, or V19, is a soluble resistance-related calcium-binding protein that is expressed in normal mammalian tissues, such as the liver, lungs and heart. It contains a flexible glycine and proline-rich N-terminal extension and five EF-hand motifs that associate with membranes in a calcium-dependent manner. It may harbor three potential Ca2+ binding sites through its EF1, EF2 and EF3 hands. However, binding of only two Ca2+/monomer suffices to trigger the conformational change that exposes hydrophobic regions and leads to interaction with the respective targets. Sorcin forms homodimers through the association of the unpaired EF5 hand. Among the PEF proteins, sorcin is unique in that it contains potential phosphorylation sites by cAMP-dependent protein kinase (PKA), and it can form a tetramer at slightly acid pH values although remaining a stable dimer at neutral pH. Grancalcin (GCA) is a cytosolic Ca2+-binding protein specifically expressed in neutrophils and monocytes/macrophages. It can strongly interact with sorcin to form a heterodimer and further modulate the function of sorcin. GCA exists as homodimers in solution. It contains five EF-hand motifs attached to an N-terminal region of an approximately 50 residue-long segment rich in glycines and prolines. In contrast with sorcin, GCA binds two Ca2+ ions through its EF1 and EF3 hands.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 157743275  80 LDEIREAFRVLDRDGNGFISKQELGMAMRSLGYMPSEVELAIIMQRLDMdgDGQVDFDEF 139
Cdd:cd16181   69 LNQWKTTFMQYDRDRSGTVEPQELQQAIRSFGYNLSPQALNVIVKRYSK--NGRITFDDF 126

EF-hand, calcium binding motif, found in parvalbumins; 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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 157743275  81 DEIREAFRVLDRDGNGFISKQELGMAMRslGYMP-----SEVELAIIMQRLDMDGDGQVDFDEFMTI 142
Cdd:cd16253   34 ADIKKVFNILDQDKSGFIEEEELKLFLK--NFSDgarvlSDKETKNFLAAGDSDGDGKIGVDEFKSM 98

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 157743275  82 EIREAFRVLDRDGNGFISKQELGMAMrSLGYMPSEVELAIIMQRL-DMDGDGQVDFDEFM 140
Cdd:cd16185    1 ELRQWFRAVDRDRSGSIDVNELQKAL-AGGGLLFSLATAEKLIRMfDRDGNGTIDFEEFA 59

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
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 157743275  86 AFRVLDRDGNGFISKQELGMAMRSLGYMPSEVELAIIMQRLDmDGDGQVDFDEFMTIL 143
Cdd:cd16196   76 VFKLFDTDGSGSFSSFELRNALNSAGFRLSNATLNALVLRYS-NKDGRISFDDFIMCA 132

EF-hand, calcium binding motif, found in peflin and similar proteins; Peflin, also termed penta-EF hand (PEF) protein with a long N-terminal hydrophobic domain, or penta-EF hand domain-containing protein 1, 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+. In lower vertebrates, peflin may interact with transient receptor potential N (TRPN1), suggesting a potential role of peflin in fast transducer channel adaptation.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 157743275  84 REAFRVLDRDGNGFISKQELGMAMRSLGYMPSEVELAIIMQRLDMDGDGQVDFDEF 139
Cdd:cd16184   70 KQVFQQFDRDRSGSIDENELHQALSQMGYRLSPQFVQFLVSKYDPRARRSLTLDQF 125

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
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 157743275  85 EAFRVLDRDGNGFISKQELGMAMRSLGYmpSEVELAIIMQRLDMDGDGQVDFDEF 139
Cdd:cd00052    3 QIFRSLDPDGDGLISGDEARPFLGKSGL--PRSVLAQIWDLADTDKDGKLDKEEF 55

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157743275  62 SLSAGSDSEQLAnisvEELdeireaFRVLDRDGNGFISKQELGMAMRSLGYMPSEVELAIIMQRLDMDGDGQVDFDEFMT 141
Cdd:NF041410  18 SSTSSARSQQFQ----KQL------FAKLDSDGDGSVSQDELSSALSSKSDDGSLIDLSELFSDLDSDGDGSLSSDELAA 87

                 ....
gi 157743275 142 ILGP 145
Cdd:NF041410  88 AAPP 91

EF-hand, calcium binding motif, found in calumenin, reticulocalbin-1 (RCN-1), reticulocalbin-3 (RCN-3), and similar proteins; The family corresponds to a group of six EF-hand Ca2+-binding proteins, including calumenin (also known as crocalbin or CBP-50), reticulocalbin-1 (RCN-1), reticulocalbin-3 (RCN-3), and similar proteins. Calumenin is an endo/sarcoplasmic reticulum (ER/SR) resident low-affinity Ca2+-binding protein that contains six EF-hand domains and a C-terminal SR retention signal His-Asp-Glu-Phe (HDEF) tetrapeptide. It functions as a novel regulator of SERCA2, and its expressional changes are tightly coupled with Ca2+-cycling of cardiomyocytes. It is also broadly involved in haemostasis and in the pathophysiology of thrombosis. Moreover, the extracellular calumenin acts as a suppressor of cell migration and tumor metastasis. RCN-1 is an endoplasmic reticulum resident Ca2+-binding protein with a carboxyl-terminal His-Asp-Glu-Leu (HDEL) tetrapeptide signal. It acts as a potential negative regulator of B-RAF activation and can negatively modulate cardiomyocyte hypertrophy by inhibition of the mitogen-activated protein kinase signalling cascade. It also plays a key role in the development of doxorubicin-associated resistance. RCN-3 is a putative six EF-hand Ca2+-binding protein that contains five RXXR (X is any amino acid) motifs and a C-terminal ER retrieval signal HDEL tetrapeptide. The RXXR motif represents the target sequence of subtilisin-like proprotein convertases (SPCs). RCN-3 is specifically bound to the paired basic amino-acid-cleaving enzyme-4 (PACE4) precursor protein and plays an important role in the biosynthesis of PACE4.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 157743275  81 DEIReaFRVLDRDGNGFISKQELGMAM--RSLGYMpSEVELAIIMQRLDMDGDGQVDFDEFM 140
Cdd:cd16226  121 DERR--WKAADQDGDGKLTKEEFTAFLhpEEFPHM-RDIVVQETLEDIDKNKDGFISLEEYI 179

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.

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                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 157743275  87 FRVLDRDGNGFISKQELGMAMrSLGYM----PSEVELAIIMqrLDMDGDGQVDFDEF 139
Cdd:cd16183    6 FQRVDKDRSGQISATELQQAL-SNGTWtpfnPETVRLMIGM--FDRDNSGTINFQEF 59

EF-hand motif found in phosphoinositide phospholipase C delta (PI-PLC-delta); PI-PLC-delta isozymes represent a class of metazoan PI-PLCs that are some of the most sensitive to calcium among all PLCs. Their activation is modulated by intracellular calcium ion concentration, phospholipids, polyamines, and other proteins, such as RhoAGAP. Like other PI-PLC isozymes, PI-PLC-delta isozymes contain 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 C-terminal C2 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. There are three PI-PLC-delta isozymes (1, 3 and 4). PI-PLC-delta1 is relatively well characterized. It is activated by high calcium levels generated by other PI-PLC family members, and therefore functions as a calcium amplifier within the cell. Different PI-PLC-delta isozymes have different tissue distribution and different subcellular locations. PI-PLC-delta1 is mostly a cytoplasmic protein, PI-PLC-delta3 is located in the membrane, and PI-PLC-delta4 is predominantly detected in the cell nucleus. PI-PLC-delta isozymes is evolutionarily conserved even in non-mammalian species, such as yeast, slime molds and plants.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157743275  83 IREAFRVLDRDGNGFISKQELGMAMRSLGYMPSEVELAIIMQRLDMDGDGQVDFDEFMTILGPKLVSSEgrdgflgntID 162
Cdd:cd16202    2 LKDQFRKADKNGDGKLSFKECKKLLKKLNVKVDKDYAKKLFQEADTSGEDVLDEEEFVQFYNRLTKRPE---------IE 72

                         90       100
                 ....*....|....*....|....
gi 157743275 163 SIFWQF--DMQRITLEELKHILYH 184
Cdd:cd16202   73 ELFKKYsgDDEALTVEELRRFLQE 96

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).

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157743275  58 YLNRSLS-AGSDSEQLANISVEE----LDEIREAFRVLDRDGNGFISKQELgmamrSLGYMPSE------VELAIIMQRL 126
Cdd:cd16227   94 YLADSFGyDDEDNEEMIKDSTEDdlklLEDDKEMFEAADLNKDGKLDKTEF-----SAFQHPEEyphmhpVLIEQTLRDK 168

                         90
                 ....*....|....
gi 157743275 127 DMDGDGQVDFDEFM 140
Cdd:cd16227  169 DKDNDGFISFQEFL 182

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 157743275   122 IMQRLDMDGDGQVDFDEFMTIL 143
Cdd:smart00054   5 AFRLFDKDGDGKIDFEEFKDLL 26

EF-hand, calcium binding motif, found in the hexa-EF hand proteins family; The hexa-EF hand proteins family, also named the calbindin sub-family, contains a group of six EF-hand Ca2+-binding proteins, including calretinin (CR, also termed 29 kDa calbindin), calbindin D28K (CB, also termed vitamin D-dependent calcium-binding protein, avian-type), and secretagogin (SCGN). CR 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 is a multifunctional protein implicated in many biological processes, including cell proliferation, differentiation, and cell death. CB is highly expressed in brain tissue. It is a strong calcium-binding and buffering protein responsible for preventing a neuronal death as well as maintaining and controlling calcium homeostasis. 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 Ca2+ sensor/coincidence detector modulating vesicular exocytosis of neurotransmitters, neuropeptides or hormones. Although the family members share a significant amount of secondary sequence homology, they display altered structural and biochemical characteristics, and operate in distinct fashions. CB contains six EF-hand motifs in a single globular domain, where EF-hands 1, 3, 4, 5 bind four calcium ions. CR contains six EF-hand motifs within two independent domains, CR I-II and CR III-VI. They harbor two and four EF-hand motifs, respectively. The first 5 EF-hand motifs are capable of binding calcium ions, while the EF-hand 6 is inactive. SCGN consists of the three globular domains each of which contains a pair of EF-hand motifs. Human SCGN simultaneously binds four calcium ions through its EF-hands 3, 4, 5 and 6 in one high affinity and three low affinity calcium-binding sites. In contrast, SCGNs in other lower eukaryotes, such as D. rerio, X. laevis, M. domestica, G. gallus, O. anatinus, are fully competent in terms of six calcium-binding.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157743275  82 EIREAFRVLDRDGNGFISKQELGMAMRSL------GYMPSEVELAI--IMQRLDMDGDGQVDFDEFMTILGPKLVSSEGR 153
Cdd:cd15902   91 EFMKIWRKYDTDGSGFIEAKELKGFLKDLllknkkHVSPPKLDEYTklILKEFDANKDGKLELDEMAKLLPVQENFLLKF 170

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 157743275 154 DGFLG-----NTIDSIFWQFDMQR---ITLEELKHIL 182
Cdd:cd15902  171 QILGAmdltkEDFEKVFEHYDKDNngvIEGNELDALL 207

Penta-EF hand, calcium binding motifs, found in calcium-dependent protease small subunit CAPNS1 and CAPNS2; CAPNS1, also termed calpain small subunit 1 (CSS1), or calcium-activated neutral proteinase small subunit (CANP small subunit), or calcium-dependent protease small subunit (CDPS), or calpain regulatory subunit, is a common 28-kDa regulatory calpain subunit encoded by the calpain small 1 (Capns1, also known as Capn4) gene. It acts as a binding partner to form a heterodimer with the 80 kDa calpain large catalytic subunit and is required in maintaining the activity of calpain. CAPNS1 plays a significant role in tumor progression of human cancer, and functions as a potential therapeutic target in human hepatocellular carcinoma (HCC), nasopharyngeal carcinoma (NPC), glioma, and clear cell renal cell carcinoma (ccRCC). It may be involved in regulating migration and cell survival through binding to the SH3 domain of Ras GTPase-activating protein (RasGAP). It may also modulate Akt/FoxO3A signaling and apoptosis through PP2A. CAPNS1 contains an N-terminal glycine rich domain and a C-terminal PEF-hand domain. CAPNS2, also termed calpain small subunit 2 (CSS2), is a novel tissue-specific 30 kDa calpain small subunit that lacks two oligo-Gly stretches characteristic of the N-terminal Gly-rich domain of CAPNS1. CAPNS2 acts as a chaperone for the calpain large subunit, and appears to be the functional equivalent of CAPNS1. However, CAPNS2 binds the large subunit much more weakly than CAPNS1 and it does not undergo the autolytic conversion typical of CAPNS1.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157743275  61 RSLSAGSDSEQLANISVEEL----DEIRE---AFRVLDRDGNGFISKQELGMAMRSLGYMPSEVELAIIMQRLDmDGDGQ 133
Cdd:cd16188   46 RSMVAVMDSDTTGKLGFEEFkylwNNIKKwqgIYKQFDTDRSGTIGSQELPGAFEAAGFHLNEQLYQMIIRRYS-DEDGN 124

                         90
                 ....*....|
gi 157743275 134 VDFDEFMTIL 143
Cdd:cd16188  125 MDFDNFISCL 134