EF-hand domain;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 281362605   30 EAAFALFDDDNAKVIPIKLLRDCLRAVAHN-PPENEIQDYITEIDTDG-SGELYLSDFLYIMSKRY 93
Cdd:pfam14658   1 ESTFEVCDTQKTGRVPVSRLIDYLRAVTGQdPQESRLQTLARELDPDGeDALVDLDTFLRVMRDWI 66

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 281362605  64 EIQDYITEIDTDGSGELYLSDFLYIMSKRYENLTvEDEVILAFKVFDKDGSGFIHENEFRQIMT 127
Cdd:cd00051    1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLS-EEEIDEMIREVDKDGDGKIDFEEFLELMA 63

centrin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281362605  21 LNDEQLKDCEAAFALFDDDNAKVIPIKLLRDCLRAVAHNPPENEIQDYITEIDTDGSGELYLSDFLYIMSKRYENLTVED 100
Cdd:PTZ00183  11 LTEDQKKEIREAFDLFDTDGSGTIDPKELKVAMRSLGFEPKKEEIKQMIADVDKDGSGKIDFEEFLDIMTKKLGERDPRE 90

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 281362605 101 EVILAFKVFDKDGSGFIHENEFRQIMTEYGDEMEEDEIEEMIRDADANTELKIDYVRFVTMMMET 165
Cdd:PTZ00183  91 EILKAFRLFDDDKTGKISLKNLKRVAKELGETITDEELQEMIDEADRNGDGEISEEEFYRIMKKT 155

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281362605  23 DEQLKDCEAAFALFDDDNAKVIPikllRDCLRAVAHNppenEIQDYITEIDTDGSGELYLSDFLYIMSKRYENlTVEDEV 102
Cdd:COG5126    1 DLQRRKLDRRFDLLDADGDGVLE----RDDFEALFRR----LWATLFSEADTDGDGRISREEFVAGMESLFEA-TVEPFA 71

                         90       100
                 ....*....|....*....|....*...
gi 281362605 103 ILAFKVFDKDGSGFIHENEFRQIMTEYG 130
Cdd:COG5126   72 RAAFDLLDTDGDGKISADEFRRLLTALG 99

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 281362605 101 EVILAFKVFDKDGSGFIHENEFRQIMTEYGDEMEEDEIEEMIRDADANTELKIDYVRFVTMMM 163
Cdd:cd00051    1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281362605  28 DCEAAFALFDDDNAKVIPIKLLRDCLRAVAHNPPENEIQDYITEIDTDGSGELYLSDFLyimsKRYENLTVEDEVI-LAF 106
Cdd:COG5126   34 LWATLFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDLLDTDGDGKISADEFR----RLLTALGVSEEEAdELF 109

                         90       100
                 ....*....|....*....|...
gi 281362605 107 KVFDKDGSGFIHENEFRQIMTEY 129
Cdd:COG5126  110 ARLDTDGDGKISFEEFVAAVRDY 132

EF-hand domain;

                          10        20
                  ....*....|....*....|....*.
gi 281362605  105 AFKVFDKDGSGFIHENEFRQIMTEYG 130
Cdd:pfam13405   5 AFKLFDKDGDGKISLEELRKALRSLG 30

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 281362605  101 EVILAFKVFDKDGSGFIHENEFRQIMTE 128
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELLKK 28

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 281362605  73 DTDGSGELYLSDFLyimsKRYENLTVEDEVilaFKVFDKDGSGFIHENEFRQIMTEYG 130
Cdd:cd16196   51 DVDRSGKLGFEEFK----KLWEDLRSWKRV---FKLFDTDGSGSFSSFELRNALNSAG 101

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 281362605  99 EDEVILAFKVFDKDGSGFIHENEFRQIMTEY---GDEMEEDEIEEMIRDADANTELKIDYVRFVTMMME 164
Cdd:cd16251   33 EDQIKKVFQILDKDKSGFIEEEELKYILKGFsiaGRDLTDEETKALLAAGDTDGDGKIGVEEFATLVAG 101

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 281362605  69 ITEIDTDGSGELYLSDFLYImskrYENLTVEDEVilaFKVFDKDGSGFIHENEFRQIMTEYG 130
Cdd:cd15897   46 IAMMDRDHSGKLNFSEFKGL----WNYIKAWQEI---FRTYDTDGSGTIDSNELRQALSGAG 100