calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20130261    7 NELTNEHIDELRDAFEKYDLDSNGTLSANEVRLALISVGYEITEAELYDLIHSVAVRDEERLDLKKFIRMMAPRMANVDS 86
Cdd:PTZ00184   3 DQLTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLMARKMKDTDS 82

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 20130261   87 DKSLCRTFNMIDRDRDGYVTVQDVRAIMVVLGEVVTDDDIKDICQAVDMDGDGRISLRDFVGFMHS 152
Cdd:PTZ00184  83 EEEIKEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEFVKMMMS 148

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20130261    7 NELTNEHIDELRDAFEKYDLDSNGTLSANEVRLALISVGYEITEAELYDLIHSVAVRDEERLDLKKFIRMMAPRMANVDS 86
Cdd:PTZ00184   3 DQLTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLMARKMKDTDS 82

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 20130261   87 DKSLCRTFNMIDRDRDGYVTVQDVRAIMVVLGEVVTDDDIKDICQAVDMDGDGRISLRDFVGFMHS 152
Cdd:PTZ00184  83 EEEIKEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEFVKMMMS 148

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 20130261  92 RTFNMIDRDRDGYVTVQDVRAIMVVLGEVVTDDDIKDICQAVDMDGDGRISLRDFVGFMH 151
Cdd:cd00051   4 EAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

Eps15 homology domain; Pair of EF hand motifs that recognise proteins containing Asn-Pro-Phe (NPF) sequences.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 20130261     94 FNMIDRDRDGYVTVQDVRAIMVVLGevVTDDDIKDICQAVDMDGDGRISLRDFVGFMH 151
Cdd:smart00027  16 FRSLDKNQDGTVTGAQAKPILLKSG--LPQTLLAKIWNLADIDNDGELDKDEFALAMH 71

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20130261    7 NELTNEHIDELRDAFEKYDLDSNGTLSANEVRLALISVGYEITEAELYDLIHSVAVRDEERLDLKKFIRMMAPRMANVDS 86
Cdd:PTZ00184   3 DQLTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLMARKMKDTDS 82

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 20130261   87 DKSLCRTFNMIDRDRDGYVTVQDVRAIMVVLGEVVTDDDIKDICQAVDMDGDGRISLRDFVGFMHS 152
Cdd:PTZ00184  83 EEEIKEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEFVKMMMS 148

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20130261  12 EHIDELRDAFEKYDLDSNGTLSANEVRLALisvgyeitEAELYDLIHSVAVRDEERLDLKKFIRMMAPRMANVDsDKSLC 91
Cdd:COG5126   2 LQRRKLDRRFDLLDADGDGVLERDDFEALF--------RRLWATLFSEADTDGDGRISREEFVAGMESLFEATV-EPFAR 72

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 20130261  92 RTFNMIDRDRDGYVTVQDVRAIMVVLGevVTDDDIKDICQAVDMDGDGRISLRDFVGFMHS 152
Cdd:COG5126  73 AAFDLLDTDGDGKISADEFRRLLTALG--VSEEEADELFARLDTDGDGKISFEEFVAAVRD 131

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 20130261    87 DKSLCRTFNMIDRDRDGYVTVQDVRAIM--VVLGEVVTDDDIKDICQAVDMDGDGRISLRDFVGFM 150
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLrkLEEGEPLSDEEVEELFKEFDLDKDGRISFEEFLELY 66

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 20130261  17 LRDAFEKYDLDSNGTLSANEVRLALISVGYEITEAELYDLIHSVavrDEER---LDLKKFIRMMApRMANVDsdkslcRT 93
Cdd:cd16185  68 MQNGFEQRDTSRSGRLDANEVHEALAASGFQLDPPAFQALFRKF---DPDRggsLGFDDYIELCI-FLASAR------NL 137

                        90
                ....*....|....
gi 20130261  94 FNMIDRDRDGYVTV 107
Cdd:cd16185 138 FQAFDRQRTGRVTL 151

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 20130261  69 DLKKFIRMMAPRMANVDSDKSLCRTFNMIDRDRDGYVTVQDVRAIMVVLGEV-----VTDDDIKDICQAVDMDGDGRISL 143
Cdd:cd16252  18 NYSKFFEYMQKFQTSEQQEEAIRKAFQMLDKDKSGFIEWNEIKYILSTVPSSmpvapLSDEEAEAMIQAADTDGDGRIDF 97

                ...
gi 20130261 144 RDF 146
Cdd:cd16252  98 QEF 100

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 20130261  61 AVRDEERLDLKKFIRMMAPRMANVDSDKslcRTFNMIDRDRDGYVTVQDVRAIMVVL---GEVVTDDDIKDICQAVDMDG 137
Cdd:cd16251  10 AFRAHGSFNYKKFFEHVGLKQKSEDQIK---KVFQILDKDKSGFIEEEELKYILKGFsiaGRDLTDEETKALLAAGDTDG 86

                ....*....
gi 20130261 138 DGRISLRDF 146
Cdd:cd16251  87 DGKIGVEEF 95

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 20130261  14 IDELRDAFEKYDLDSNGTLSANEVRLALISVGYEITEaELYDLIHSVAVRDEERLDLKKFIRMMAPRMAnvdsdksLCRT 93
Cdd:cd15897  69 IKAWQEIFRTYDTDGSGTIDSNELRQALSGAGYRLSE-QTYDIIIRRYDRGRGNIDFDDFIQCCVRLQR-------LTDA 140

                        90
                ....*....|....
gi 20130261  94 FNMIDRDRDGYVTV 107
Cdd:cd15897 141 FRRYDKDQDGQIQV 154

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20130261  12 EHIDELRDAFEKYDLDSNGTLSANEVRLALISVGYEITEaELYDLIhsvavrdeerldLKKFIRMMAPRMANVD------ 85
Cdd:cd16183  64 KYITDWQNCFRSFDRDNSGNIDKNELKQALTSFGYRLSD-QFYDIL------------VRKFDRQGRGTIAFDDfiqccv 130

                        90       100
                ....*....|....*....|...
gi 20130261  86 SDKSLCRTFNMIDRDRDGYVTVQ 108
Cdd:cd16183 131 VLQTLTDSFRRYDTDQDGWIQIS 153

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 20130261    14 IDELRDAFEKYDLDSNGTLSANEVRLAL--ISVGYEITEAELYDLIHSVAVRDEERLDLKKFIRMM 77
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLrkLEEGEPLSDEEVEELFKEFDLDKDGRISFEEFLELY 66

EF-hand, calcium binding motif, found in reticulocalbin-3 (RCN-3); RCN-3, also termed EF-hand calcium-binding protein RLP49, 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 His-Asp-Glu-Leu (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        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20130261  15 DELRDAFEKYDLDSNGTLSANEVRLALI---SVGYEITEAELYDLIHSVAVRDEERLDL-----------KKFIRMMAPR 80
Cdd:cd16230  73 DSVSAAWQTYDTDRDGRVGWEELRNATYghyEPGEEFHDVEDAETYKKMLARDERRFRVadqdgdsmatrEELTAFLHPE 152

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 20130261  81 MANVDSDKSLCRTFNMIDRDRDGYVTVQDVRAIMVVlGEVVTDD------DIKDICQAVDMDGDGRI 141
Cdd:cd16230 153 EFPHMRDIVVAETLEDLDKNKDGYVQVEEYIADLYS-GEPGEEEpawvqtERQQFRQFRDLNKDGRL 218

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 20130261  61 AVRDEERLDLKKFIRMMAPRMANVDSDKslcRTFNMIDRDRDGYVTVQDVRAIMVVL---GEVVTDDDIKDICQAVDMDG 137
Cdd:cd16254  10 AFAAADSFDYKKFFEMVGLKKKSADDVK---KVFHILDKDKSGFIEEDELKFVLKGFspdGRDLSDKETKALLAAGDKDG 86

                        90
                ....*....|....
gi 20130261 138 DGRISLRDFVGFMH 151
Cdd:cd16254  87 DGKIGIDEFATLVA 100

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20130261  61 AVRDEERLDLKKFI------RMMAPRMANVdsdkslcrtFNMIDRDRDGYVTVQDVRAIMVVL---GEVVTDDDIKDICQ 131
Cdd:cd16255  10 QCQAADSFNFKKFFatsglsKKSADDVKKV---------FEIIDQDKSGFIEEEELKLFLQNFssgARELTDAETKAFLK 80

                        90       100
                ....*....|....*....|.
gi 20130261 132 AVDMDGDGRISLRDFVGFMHS 152
Cdd:cd16255  81 AGDSDGDGKIGVEEFQALVKA 101

Penta-EF hand, calcium binding motifs, found in calpain-12 (CAPN12); CAPN12, also termed calcium-activated neutral proteinase 12 (CANP 12), is a calpain large subunit mainly expressed in the cortex of the hair follicle. It may affect apoptosis regulation. CAPN12 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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20130261  12 EHIDELRDAFEKYDLDSNGTLSANEVRLALISVGYEITEaELYDLIHSVAVRDEERLDLKKFIRMMAPRMAnvdsdkSLC 91
Cdd:cd16194  70 GYLLEWQAIFTKFDEDTSGTMDSYELRLALNAAGFHLNN-QLTETLTSRYRDSRLRVDFESFLSCLAHLTC------IFC 142

                        90
                ....*....|....*.
gi 20130261  92 RTFNMiDRDRDGYVTV 107
Cdd:cd16194 143 QCSQH-DDGGEGVICL 157

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

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 20130261  92 RTFNMIDRDRDGYVTVQDVRAIMvvlgevvtDDDIKDICQAVDMDGDGRISLRDFVGFMHSP 153
Cdd:COG5126   9 RRFDLLDADGDGVLERDDFEALF--------RRLWATLFSEADTDGDGRISREEFVAGMESL 62

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
                ....*....|....*....|....*....|....*....|....*..
gi 20130261  18 RDAFEKYDLDSNGTLSANEVRLALISVGYEITEAELYDLIHSVAVRD 64
Cdd:cd16196  74 KRVFKLFDTDGSGSFSSFELRNALNSAGFRLSNATLNALVLRYSNKD 120

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        60
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 20130261  14 IDELRDAFEKYDLDSNGTLSANEVRLALISVGYEITEAELYDLIHSVAVRDEERLDLKKFI 74
Cdd:cd16184  66 IQQWKQVFQQFDRDRSGSIDENELHQALSQMGYRLSPQFVQFLVSKYDPRARRSLTLDQFI 126

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        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 20130261  13 HIDELRDAFEKYDLDSNGTLSANEVRLALISVGYEITEaelyDLIHSVAVR---DEERLDLKKFIRMM 77
Cdd:cd16195  71 KLRKYKDIFQKADVSKSGFLSLSELRNAIQAAGIRVSD----DLLNLMALRygdSSGRISFESFICLM 134

N-terminal domain of Myosin essential light chain ELC; ELC is part of the apicomplexan membrane-associated protein complex called the glideosome, which is essential for parasite motility. The glideosome is composed of six proteins: myosin A (MyoA), essential light chain ELC, myosin light chain MLC1 (also called MTIP), and the glideosome-associated proteins GAP40, GAP45, and GAP50. MyoA is a Class XIV myosin implicated in gliding motility, as well as host cell and tissue invasion by parasites. ELC binds to the MyoA neck region adjacent to the MLC1-binding site, and both myosin light chains co-located to the glideosome. Although ELCs bind to a conserved MyoA sequence, P. falciparum ELC adopts a distinct structure in the free and MyoA-bound state. Therefore ELCs enhance MyoA performance by inducing alpha helical structure formation in MyoA and thus stiffening its lever arm. It has been shown that disruption of MyoA, MLC1, or ELC have dramatic effects on parasite motility but do not affect parasite shape or replication. The ELC N-terminal domain is part of the EF-hand calcium binding motif superfamily. Calcium binding has no effect on the structure of ELCs.

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gi 20130261  15 DELRDAFEKYDLDSNGTLSANEVRLALISVGYEITEAELYDLIHSVAVRDEERLDLKKF 73
Cdd:cd22949   3 EKFREAFILFDRDGDGELTMYEAVLAMRSCGIPLTNDEKDALPASMNWDQFENWAKKKL 61