calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15221284    4 DGLSDDQVSSMKEAFMLFDTDGDGKIAPSELGILMRSLGGNPTQAQLKSIIAS--ENLSSPFDFNRFLDLMAKHLKTEPF 81
Cdd:PTZ00184   3 DQLTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEvdADGNGTIDFPEFLTLMARKMKDTDS 82

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 15221284   82 DRQLRDAFKVLDKEGTGFVAVADLRHILTSIGEKLEPNEFDEWIKEVDVGSDGKIRYEDFIARMVAK 148
Cdd:PTZ00184  83 EEEIKEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEFVKMMMSK 149

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15221284    4 DGLSDDQVSSMKEAFMLFDTDGDGKIAPSELGILMRSLGGNPTQAQLKSIIAS--ENLSSPFDFNRFLDLMAKHLKTEPF 81
Cdd:PTZ00184   3 DQLTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEvdADGNGTIDFPEFLTLMARKMKDTDS 82

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 15221284   82 DRQLRDAFKVLDKEGTGFVAVADLRHILTSIGEKLEPNEFDEWIKEVDVGSDGKIRYEDFIARMVAK 148
Cdd:PTZ00184  83 EEEIKEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEFVKMMMSK 149

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 15221284  84 QLRDAFKVLDKEGTGFVAVADLRHILTSIGEKLEPNEFDEWIKEVDVGSDGKIRYEDFIARM 145
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELM 62

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 15221284     14 MKEAFMLFDTDGDGKIAPSELGILMRSL 41
Cdd:smart00054   2 LKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15221284    4 DGLSDDQVSSMKEAFMLFDTDGDGKIAPSELGILMRSLGGNPTQAQLKSIIAS--ENLSSPFDFNRFLDLMAKHLKTEPF 81
Cdd:PTZ00184   3 DQLTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEvdADGNGTIDFPEFLTLMARKMKDTDS 82

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 15221284   82 DRQLRDAFKVLDKEGTGFVAVADLRHILTSIGEKLEPNEFDEWIKEVDVGSDGKIRYEDFIARMVAK 148
Cdd:PTZ00184  83 EEEIKEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEFVKMMMSK 149

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 15221284    82 DRQLRDAFKVLDKEGTGFVAVADLRHILTSI--GEKLEPNEFDEWIKEVDVGSDGKIRYEDFIARM 145
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRKLeeGEPLSDEEVEELFKEFDLDKDGRISFEEFLELY 66

EF-hand, calcium binding motif, found in uncharacterized calglandulin-like proteins; The family corresponds to a group of uncharacterized calglandulin-like proteins. Although their biological function remain unclear, they show high sequence similarity with human calglandulin-like protein GAGLP, which is an ortholog of calglandulin from the venom glands of Bothrops insularis snake. Both GAGLP and calglandulin are putative Ca2+-binding proteins with four EF-hand motifs. However, members in this family contain only three EF-hand motifs. In this point, they may belong to the parvalbumin-like EF-hand family, which is characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15221284  63 FDFNRFLDLMAKHLKTEPFDRQLRDAFKVLDKEGTGFVAVADLRHILTSIGEK-----LEPNEFDEWIKEVDVGSDGKIR 137
Cdd:cd16252  17 FNYSKFFEYMQKFQTSEQQEEAIRKAFQMLDKDKSGFIEWNEIKYILSTVPSSmpvapLSDEEAEAMIQAADTDGDGRID 96

                ....
gi 15221284 138 YEDF 141
Cdd:cd16252  97 FQEF 100

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 15221284  15 KEAFMLFDTDGDGKIAPSELGILMRSLGGNPTQAQLKSIIAS--ENLSSPFDFNRFLDLMA 73
Cdd:cd00051   3 REAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREvdKDGDGKIDFEEFLELMA 63

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 15221284  50 LKSIIASENLSSPFDFNRFLDLMAKHLKTEPfdrQLRDAFKVLDKEGTGFVAVADLRHIL---TSIGEKLEPNEFDEWIK 126
Cdd:cd16251   4 IEKAPSAFRAHGSFNYKKFFEHVGLKQKSED---QIKKVFQILDKDKSGFIEEEELKYILkgfSIAGRDLTDEETKALLA 80

                        90       100
                ....*....|....*....|.
gi 15221284 127 EVDVGSDGKIRYEDFiARMVA 147
Cdd:cd16251  81 AGDTDGDGKIGVEEF-ATLVA 100

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        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15221284  15 KEAFMLFDTDGDGKIAPSELGILMRSLGGNPTQAQLKSIIA--SENLSSPFDfnrflDLMAKHLKTepfdRQLRDAFKVL 92
Cdd:cd16181  73 KTTFMQYDRDRSGTVEPQELQQAIRSFGYNLSPQALNVIVKrySKNGRITFD-----DFVACAVRL----RALTDRFRRR 143

                ....*....
gi 15221284  93 DKEGTGFVA 101
Cdd:cd16181 144 DTQQNGTAT 152

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 15221284     14 MKEAFMLFDTDGDGKIAPSELGILMRSL 41
Cdd:smart00054   2 LKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

EF-hand domain;

                          10        20        30
                  ....*....|....*....|....*....|
gi 15221284    84 QLRDAFKVLDKEGTGFVAVADLRHILTSIG 113
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKALRSLG 30

Penta-EF hand, calcium binding motifs, found in PEF calpain family; The PEF calpain family belongs to the second group of penta-EF hand (PEF) proteins. It includes classical (also called conventional or typical) calpain (referring to a calcium-dependent papain-like enzymes, EC 3.4.22.17) large catalytic subunits (CAPN1, 2, 3, 8, 9, 11, 12, 13, 14) and two calpain small subunits (CAPNS1 and CAPNS2), which are largely confined to animals (metazoans). These PEF-containing are nonlysosomal intracellular calcium-activated intracellular cysteine proteases that play important roles in the degradation or functional modulation in a variety of substrates in response to calcium signalling. The classical mu- and m-calpains are heterodimers consisting of homologous but a distinct (large) L-subunit/chain (CAPN1 or CAPN2) and a common (small) S-subunit/chain (CAPNS1 or CAPNS2). These L-subunits (CAPN1 and CAPN2) and S-subunit CAPNS1 are ubiquitously found in all tissues. Other calpains likely consist of an isolated L-subunit/chain alone. Many of them, such as CAPNS2, CAPN3 (in skeletal muscle, or lens), CAPN8 (in stomach), CAPN9 (in digestive tracts), CAPN11 (in testis), CAPN12 (in follicles), are tissue-specific and have specific functions in distinct organs. The L-subunits of similar structure (called CALPA and B) also have been found in Drosophila melanogaster. The S-subunit seems to have a chaperone-like function for proper folding of the L-subunit. The catalytic L-subunits 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 S-subunits only have the PEF domain following an N-terminal Gly-rich hydrophobic domain. The calpains undergo a rearrangement of the protein backbone upon Ca2+-binding.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15221284  24 DGDGKIAPSELGILMRSL----GGNPTQAQL---KSIIASE--NLSSPFDFNRFLDLMaKHLKtepfdrQLRDAFKVLDK 94
Cdd:cd16182  11 GEDEEIDAVELQKLLNASllkdMPKFDGFSLetcRSLIALMdtNGSGRLDLEEFKTLW-SDLK------KWQAIFKKFDT 83

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|..
gi 15221284  95 EGTGFVAVADLRHILTSIGEKLePNEFDEWIKEVDVGSDGKIRYEDFIARMV 146
Cdd:cd16182  84 DRSGTLSSYELRKALESAGFHL-SNKVLQALVLRYADSTGRITFEDFVSCLV 134

Penta-EF hand, calcium binding motifs, found in grancalcin; Grancalcin (GCA) is a cytosolic Ca2+-binding protein specifically expressed in neutrophils and monocytes/macrophages. It displays a Ca2+-dependent translocation to granules and plasma membrane upon neutrophil activation, suggesting roles in granule-membrane fusion and degranulation of neutrophils. It may also play a role in the regulation of vesicle/granule exocytosis through the reversible binding of secretory vesicles and plasma membranes upon the presence of calcium. Moreover, GCA is involved in inflammation, as well as in the process of adhesion of neutrophils to fibronectin. It plays a key role in leukocyte-specific functions that are responsible for host defense, and affects the function of integrin receptors on immune cells through binding to L-plastin in the absence of calcium. Furthermore, GCA 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. GCA binds two Ca2+ ions through its EF1 and EF3 hands.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15221284  11 VSSMKEAFMLFDTDGDGKIAPSELGILMRSLGGNPTQAQLKSIIA--SENLSSPFDfnrflDLMAKHLKTepfdRQLRDA 88
Cdd:cd16186  69 LNAWKQNFMTVDQDRSGTVEPHELRQAIGAMGYRLSPQTLTTIVKrySKNGRIYFD-----DYVACCVKL----RALTDF 139

                        90
                ....*....|..
gi 15221284  89 FKVLDKEGTGFV 100
Cdd:cd16186 140 FRRRDHMQQGSV 151

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 15221284  16 EAFMLF---DTDGDGKIAPSELGILMRSlgGNPTQAQLKSI-----IASENLSSPFDFNRFLDLMaKHLktepfdRQLRD 87
Cdd:cd16180   1 ELRRIFqavDRDRSGRISAKELQRALSN--GDWTPFSIETVrlminMFDRDRSGTINFDEFVGLW-KYI------QDWRR 71

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*
gi 15221284  88 AFKVLDKEGTGFVAVADLRHILTSIGEKLEPNEFDEWIKEVDVGSDGKIRYEDFI 142
Cdd:cd16180  72 LFRRFDRDRSGSIDFNELQNALSSFGYRLSPQFVQLLVRKFDRRRRGSISFDDFV 126

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 15221284  63 FDFNRFLDLMAKHLKTepfDRQLRDAFKVLDKEGTGFVAVADLRHIL---TSIGEKLEPNEFDEWIKEVDVGSDGKIRYE 139
Cdd:cd16254  17 FDYKKFFEMVGLKKKS---ADDVKKVFHILDKDKSGFIEEDELKFVLkgfSPDGRDLSDKETKALLAAGDKDGDGKIGID 93

                ....*....
gi 15221284 140 DFIArMVAK 148
Cdd:cd16254  94 EFAT-LVAE 101