calmodulin; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2194856123   5 VEEFQEAFQLFDSRGDGKIHIAQIGDALRALGQNPTESDVKKFTHQHKPDER--ISFEVFLPIYQaiSKSRTSDTADDFI 82
Cdd:PTZ00184   10 IAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNgtIDFPEFLTLMA--RKMKDTDSEEEIK 87

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 2194856123  83 EGLRHFDKDGNGYISSAELRHLLTTLGEKLSDEEVETLLagHE---DSQGNINYEDFVRQIM 141
Cdd:PTZ00184   88 EAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMI--REadvDGDGQINYEEFVKMMM 147

calmodulin; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2194856123   5 VEEFQEAFQLFDSRGDGKIHIAQIGDALRALGQNPTESDVKKFTHQHKPDER--ISFEVFLPIYQaiSKSRTSDTADDFI 82
Cdd:PTZ00184   10 IAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNgtIDFPEFLTLMA--RKMKDTDSEEEIK 87

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 2194856123  83 EGLRHFDKDGNGYISSAELRHLLTTLGEKLSDEEVETLLagHE---DSQGNINYEDFVRQIM 141
Cdd:PTZ00184   88 EAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMI--REadvDGDGQINYEEFVKMMM 147

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2194856123   6 EEFQEAFQLFDSRGDGKIHIAQI-GDALRALGQNPTESDVKKfthqhkpDERISFEVFLpiyqAISKSRTSDTADDFIEG 84
Cdd:COG5126     5 RKLDRRFDLLDADGDGVLERDDFeALFRRLWATLFSEADTDG-------DGRISREEFV----AGMESLFEATVEPFARA 73

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 2194856123  85 L-RHFDKDGNGYISSAELRHLLTTLGekLSDEEVETLLAGHE-DSQGNINYEDFVR 138
Cdd:COG5126    74 AfDLLDTDGDGKISADEFRRLLTALG--VSEEEADELFARLDtDGDGKISFEEFVA 127

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 2194856123   86 RHFDKDGNGYISSAELRHLLTTL 108
Cdd:smart00054   7 RLFDKDGDGKIDFEEFKDLLKAL 29

calmodulin; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2194856123   5 VEEFQEAFQLFDSRGDGKIHIAQIGDALRALGQNPTESDVKKFTHQHKPDER--ISFEVFLPIYQaiSKSRTSDTADDFI 82
Cdd:PTZ00184   10 IAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNgtIDFPEFLTLMA--RKMKDTDSEEEIK 87

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 2194856123  83 EGLRHFDKDGNGYISSAELRHLLTTLGEKLSDEEVETLLagHE---DSQGNINYEDFVRQIM 141
Cdd:PTZ00184   88 EAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMI--REadvDGDGQINYEEFVKMMM 147

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 2194856123  80 DFIEGLRHFDKDGNGYISSAELRHLLTTLGEKLSDEEVETLLAGHeDSQGN--INYEDFVRQIM 141
Cdd:cd00051     1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREV-DKDGDgkIDFEEFLELMA 63

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 2194856123   7 EFQEAFQLFDSRgDGKIHIAQIGDALRALGQNPTESD-----VKKFTHQHKPDE--RISFEVFLPIYQAISKSRtsdtad 79
Cdd:cd15897     1 QLRNVFQAVAGD-DGEISATELQQALSNVGWTHFDLGfsletCRSMIAMMDRDHsgKLNFSEFKGLWNYIKAWQ------ 73

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 2194856123  80 dfiEGLRHFDKDGNGYISSAELRHLLTTLGEKLSDEEVETLLAGHEDSQGNINYEDFV 137
Cdd:cd15897    74 ---EIFRTYDTDGSGTIDSNELRQALSGAGYRLSEQTYDIIIRRYDRGRGNIDFDDFI 128

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 2194856123   7 EFQEAFQLFDSRGDGKIHIAQIGDALRALGQNPTESDVKKFTHQHKPDE--RISFEVFLPIYQAISKSRtsdtaddfiEG 84
Cdd:cd16185     1 ELRQWFRAVDRDRSGSIDVNELQKALAGGGLLFSLATAEKLIRMFDRDGngTIDFEEFAALHQFLSNMQ---------NG 71

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 2194856123  85 LRHFDKDGNGYISSAELRHLLTTLGEKLSDEEVETLLAGH-EDSQGNINYEDFVRqiMC 142
Cdd:cd16185    72 FEQRDTSRSGRLDANEVHEALAASGFQLDPPAFQALFRKFdPDRGGSLGFDDYIE--LC 128

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 2194856123  88 FDKDGNGYISSAELRHLLTTLGEKLSDEEVETLLAGHEDSQGNINYEDFvrqIMC 142
Cdd:cd16196    80 FDTDGSGSFSSFELRNALNSAGFRLSNATLNALVLRYSNKDGRISFDDF---IMC 131

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2194856123   6 EEFQEAFQLFDSRGDGKIHIAQIGDALralgqnPTEsdvkkfthqhkpderisfEVFLPIYQAISKSRTsdTADDFIEGL 85
Cdd:cd15902   134 EYTKLILKEFDANKDGKLELDEMAKLL------PVQ------------------ENFLLKFQILGAMDL--TKEDFEKVF 187

                          90       100
                  ....*....|....*....|....*.
gi 2194856123  86 RHFDKDGNGYISSAELRHLLTTLGEK 111
Cdd:cd15902   188 EHYDKDNNGVIEGNELDALLKDLLEK 213

Penta-EF hand, calcium binding motifs, found in calpain-13 (CAPN13), calpain-14 (CAPN14), and similar proteins; CAPN13, also termed calcium-activated neutral proteinase 13 (CANP 13), a 63.6 kDa calpain large subunit that exhibits a restricted tissue distribution with low levels of expression detected only in human testis and lung. In calpain family, CAPN13 is most closely related to calpain-14 (CAPN14). CAPN14, also termed calcium-activated neutral proteinase 14 (CANP 14), is a 76.7 kDa calpain large subunit that is most highly expressed in the oesophagus. Its expression and calpain activity can be induced by IL-13. Both CAPN13 and CAPN14 contain 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
                  ....*....|....*....|....*....|....*....|....*....|..
gi 2194856123  86 RHFDKDGNGYISSAELRHLLTTLGEKLSDEEVETLLAGHEDSQGNINYEDFV 137
Cdd:cd16195    80 QKADVSKSGFLSLSELRNAIQAAGIRVSDDLLNLMALRYGDSSGRISFESFI 131

EF-hand domain;

                          10        20        30
                  ....*....|....*....|....*....|
gi 2194856123  80 DFIEGLRHFDKDGNGYISSAELRHLLTTLG 109
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        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2194856123  59 FEVFLPIYQAISKSRTSdtaddFIEglrhFDKDGNGYISSAELRHLLTTLGEKLSDEEVETLLAGHEDsQGNINYEDFV 137
Cdd:cd16181    59 FNEFKELWAALNQWKTT-----FMQ----YDRDRSGTVEPQELQQAIRSFGYNLSPQALNVIVKRYSK-NGRITFDDFV 127

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 2194856123   6 EEFQEAFQLFDSRGDGKIHIAQIGDALRALGQNPTESD------VKKFTHQHkpDERISFEVFLPIYQ 67
Cdd:pfam13499   2 EKLKEAFKLLDSDGDGYLDVEELKKLLRKLEEGEPLSDeeveelFKEFDLDK--DGRISFEEFLELYS 67

Penta-EF hand, calcium binding motifs, found in mu-type calpain (CAPN1), m-type calpain (CAPN2), and similar proteins; The family includes mu-type calpain (CAPN1) and m-type calpain (CAPN2), both of which are ubiquitously expressed 80-kDa Ca2+-dependent intracellular cysteine proteases that contain 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. The catalytic subunit CAPN1 or CAPN2 in complex with a regulatory subunit encoded by CAPNS1 forms a mu- or m-calpain heterodimer, respectively.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 2194856123  81 FIEGLRHFDKDGNGYISSAELRHLLTTLGEKLSDEEVETLLAGHEDSQGNINYEDFVR 138
Cdd:cd16189    75 YLKIYKKFDTDGSGTMSSYEMRLALEEAGFKLNNQLHQVLVARYADQELTIDFDNFVR 132

EF-hand domain;

                          10        20        30
                  ....*....|....*....|....*....|
gi 2194856123   7 EFQEAFQLFDSRGDGKIHIAQIGDALRALG 36
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKALRSLG 30

Penta-EF hand, calcium binding motifs, found in m-type calpain (CAPN2); CAPN2, also termed millimolar-calpain (m-calpain), or calpain-2 catalytic subunit, or calcium-activated neutral proteinase 2 (CANP 2), or calpain large polypeptide L2, or calpain-2 large subunit, is a ubiquitously expressed 80-kDa Ca2+-dependent intracellular cysteine protease that 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. The catalytic subunit CAPN2 in complex with a regulatory subunit encoded by CAPNS1 forms an m-calpain heterodimer. CAPN2 acts as the key protease responsible for N-methyl-d-aspartic acid (NMDA)-induced cytoplasmic polyadenylation element-binding protein 3 (CPEB3) degradation in neurons. It cleaves several components of the focal adhesion complex, such as FAK and talin, triggering disassembly of the complex at the rear of the cell. The stimulation of CAPN2 activity is required for Golgi antiapoptotic proteins (GAAPs) to promote cleavage of FA kinase (FAK), cell spreading, and enhanced migration. calpain 2 is also involved in the onset of glial differentiation. It regulates proliferation, survival, migration, and tumorigenesis of breast cancer cells through a PP2A-Akt-FoxO-p27(Kip1) signaling cascade. Its expression is associated with response to platinum based chemotherapy, progression-free and overall survival in ovarian cancer. Moreover, CAPN2 may play a role in fundamental mitotic functions, such as the maintenance of sister chromatid cohesion. The activation of CAPN2 plays an essential role in hippocampal synaptic plasticity and in learning and memory. In the eye, CAPN2, together with a lens-specific variant of CAPN3, is responsible for proteolytic cleavages of alpha and beta-crystallin. Overactivated alpha and beta-crystallin can lead to cataract formation. Sometimes, CAPN2 compensates for loss of CAPN1, and both calpain isoforms are involved in AngII-induced aortic aneurysm formation. The main phosphorylation sites in m-calpain are Ser50 and Ser369/Thr370.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 2194856123  86 RHFDKDGNGYISSAELRHLLTTLGEKLSDEEVETLLAGHEDSQGNINYEDFVR 138
Cdd:cd16199    80 REIDVDRSGTMNSYEMRKALEEAGFKLPCQLHQVIVARFADDDLIIDFDNFVR 132

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 2194856123   86 RHFDKDGNGYISSAELRHLLTTL 108
Cdd:smart00054   7 RLFDKDGDGKIDFEEFKDLLKAL 29

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2194856123  77 TADDFIEGLRHFDKDGNGYISSAELRHLL---TTLGEKLSDEEVETLL-AGHEDSQGNINYEDF 136
Cdd:cd16254    32 SADDVKKVFHILDKDKSGFIEEDELKFVLkgfSPDGRDLSDKETKALLaAGDKDGDGKIGIDEF 95

centrin; Provisional

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 2194856123  74 TSDTADDFIEGLRHFDKDGNGYISSAELRHLLTTLGEKLSDEEVETLLAGHE-DSQGNINYEDFVRQI 140
Cdd:PTZ00183   12 TEDQKKEIREAFDLFDTDGSGTIDPKELKVAMRSLGFEPKKEEIKQMIADVDkDGSGKIDFEEFLDIM 79

Calcium-activated neutral; CAPN3, also termed calcium-activated neutral proteinase 3 (CANP 3), or calpain L3, or calpain p94, or muscle-specific calcium-activated neutral protease 3, or new calpain 1 (nCL-1), is a calpain large subunit that is mainly expressed in skeletal muscle, or lens. The skeletal muscle-specific CAPN3 are pathologically associated with limb girdle muscular dystrophy type 2A (LGMD2A). Its autolytic activity can be positively regulated by calmodulin (CaM), a known transducer of the calcium signal. CAPN3 is also involved in human melanoma tumorigenesis and progression. It impairs cell proliferation and stimulates oxidative stress-mediated cell death in melanoma cells. Moreover, it plays an important role in sarcomere remodeling and mitochondrial protein turnover. Furthermore, the phosphorylated skeletal muscle-specific CAPN3 acts as a myofibril structural component and may participate in myofibril-based signaling pathways. In the eye, the lens-specific CAPN3, together with CAPN2, is responsible for proteolytic cleavages of alpha and beta-crystallin. Overactivated alpha and beta-crystallin can lead to cataract formation. CAPN3 exists as a homodimer, rather than a heterodimer with the calpain small subunit. It may also form heterodimers with other calpain large subunits. CAPN3 contains a long N-terminal region, 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. Ca2+ binding at EF5 of the CAPN3 PEF domain is a distinct feature not observed in other calpain isoforms.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 2194856123  86 RHFDKDGNGYISSAELRHLLTTLGEKLSDEEVETLLAGHEDSQGNINYEDFV 137
Cdd:cd16190    80 KRYDTDKSGTINSYEMRNAVNDAGFRLNNQLYDIITMRYADKHMNIDFDSFI 131

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
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gi 2194856123   5 VEEFQEAFQLFDSRGDGKIHIAQIGDALRALGQnptesdvkkfthqhkpdeRISFEVFLPIYQAISKSRTSDTA-DDFIE 83
Cdd:cd16180    66 IQDWRRLFRRFDRDRSGSIDFNELQNALSSFGY------------------RLSPQFVQLLVRKFDRRRRGSISfDDFVE 127

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gi 2194856123  84 GL----------RHFDKDGNGYI 96
Cdd:cd16180   128 ACvtlkrltdafRKYDTNRTGYA 150