calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665410492   6 EDLTPEQIAVLQKAFNSFDHQKTGSIPTEMVADILRLMGQPFDKKILEELIEEVDEDKSGRLEFGEFVQLAAKFIVEEDA 85
Cdd:PTZ00184   3 DQLTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLMARKMKDTDS 82

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 665410492  86 EamqKELREAFRLYDKQGNGFIPTTCLKEILKELDDQLTEQELDIMIEEIDSDGSGTVDFDEFMEMMT 153
Cdd:PTZ00184  83 E---EEIKEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEFVKMMM 147

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665410492   6 EDLTPEQIAVLQKAFNSFDHQKTGSIPTEMVADILRLMGQPFDKKILEELIEEVDEDKSGRLEFGEFVQLAAKFIVEEDA 85
Cdd:PTZ00184   3 DQLTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLMARKMKDTDS 82

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 665410492  86 EamqKELREAFRLYDKQGNGFIPTTCLKEILKELDDQLTEQELDIMIEEIDSDGSGTVDFDEFMEMMT 153
Cdd:PTZ00184  83 E---EEIKEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEFVKMMM 147

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665410492  11 EQIAVLQKAFNSFDHQKTGSIPTEmvaDILRLMGQpfdkkILEELIEEVDEDKSGRLEFGEFVQLAAKfiveEDAEAMQK 90
Cdd:COG5126    2 LQRRKLDRRFDLLDADGDGVLERD---DFEALFRR-----LWATLFSEADTDGDGRISREEFVAGMES----LFEATVEP 69

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 665410492  91 ELREAFRLYDKQGNGFIPTTCLKEILKELDdqLTEQELDIMIEEIDSDGSGTVDFDEFMEMMTG 154
Cdd:COG5126   70 FARAAFDLLDTDGDGKISADEFRRLLTALG--VSEEEADELFARLDTDGDGKISFEEFVAAVRD 131

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 665410492   127 ELDIMIEEIDSDGSGTVDFDEFMEMMT 153
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLK 27

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665410492   6 EDLTPEQIAVLQKAFNSFDHQKTGSIPTEMVADILRLMGQPFDKKILEELIEEVDEDKSGRLEFGEFVQLAAKFIVEEDA 85
Cdd:PTZ00184   3 DQLTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLMARKMKDTDS 82

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 665410492  86 EamqKELREAFRLYDKQGNGFIPTTCLKEILKELDDQLTEQELDIMIEEIDSDGSGTVDFDEFMEMMT 153
Cdd:PTZ00184  83 E---EEIKEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEFVKMMM 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 665410492  91 ELREAFRLYDKQGNGFIPTTCLKEILKELDDQLTEQELDIMIEEIDSDGSGTVDFDEFMEMMT 153
Cdd:cd00051    1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

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 665410492  15 VLQKAFNSFDHQKTGSIPTEMVADILRLMGQPFDKKILEELIEEVDEDKSGRLEFGEFVQLaAKFIVeedaeAMQkelrE 94
Cdd:cd16185    1 ELRQWFRAVDRDRSGSIDVNELQKALAGGGLLFSLATAEKLIRMFDRDGNGTIDFEEFAAL-HQFLS-----NMQ----N 70

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 665410492  95 AFRLYDKQGNGFIPTTCLKEILKELDDQLTEQELDIMIEEIDSDGSGTVDFDEFMEM 151
Cdd:cd16185   71 GFEQRDTSRSGRLDANEVHEALAASGFQLDPPAFQALFRKFDPDRGGSLGFDDYIEL 127

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 665410492  15 VLQKAFNSFDHQKTGSIPTEMVADILRLMGQ-PFDKKILEELIEEVDEDKSGRLEFGEFVQLAaKFIveedaeamqKELR 93
Cdd:cd16180    1 ELRRIFQAVDRDRSGRISAKELQRALSNGDWtPFSIETVRLMINMFDRDRSGTINFDEFVGLW-KYI---------QDWR 70

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 665410492  94 EAFRLYDKQGNGFIPTTCLKEILKELDDQLTEQELDIMIEEIDSDGSGTVDFDEFMEMMT 153
Cdd:cd16180   71 RLFRRFDRDRSGSIDFNELQNALSSFGYRLSPQFVQLLVRKFDRRRRGSISFDDFVEACV 130

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 665410492  46 PFDKKILEELIEEVDEDKSGRLEFGEFVQLAAKFiveedaeamqKELREAFRLYDKQGNGFIPTTCLKEILKELDDQLTE 125
Cdd:cd15897   36 GFSLETCRSMIAMMDRDHSGKLNFSEFKGLWNYI----------KAWQEIFRTYDTDGSGTIDSNELRQALSGAGYRLSE 105

                         90       100
                 ....*....|....*....|....*
gi 665410492 126 QELDIMIEEIDsDGSGTVDFDEFME 150
Cdd:cd15897  106 QTYDIIIRRYD-RGRGNIDFDDFIQ 129

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 665410492  45 QPFDKKILEELIEEVDEDKSGRLEFGEFVQLAAKFiveedaeamqKELREAFRLYDKQGNGFIPTTCLKEILKELDDQLT 124
Cdd:cd16182   37 DGFSLETCRSLIALMDTNGSGRLDLEEFKTLWSDL----------KKWQAIFKKFDTDRSGTLSSYELRKALESAGFHLS 106

                         90       100
                 ....*....|....*....|....*
gi 665410492 125 EQELDIMIEEIdSDGSGTVDFDEFM 149
Cdd:cd16182  107 NKVLQALVLRY-ADSTGRITFEDFV 130

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 665410492  49 KKILEELIEEVDEDKSGRLEFGEFVQLAA------KFIVEEDAEAMQKELREAFRLYDKQGNGFIPTTCLKEILKEL--- 119
Cdd:cd15902   43 AEKKKEFMEKYDENEDGKIEIRELANILPteenflLLFRREQPLISSVEFMKIWRKYDTDGSGFIEAKELKGFLKDLllk 122

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 665410492 120 -----DDQLTEQELDIMIEEIDSDGSGTVDFDEFMEMM 152
Cdd:cd15902  123 nkkhvSPPKLDEYTKLILKEFDANKDGKLELDEMAKLL 160

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 665410492   13 IAVLQKAFNSFDHQKTGSIPTEMVADILR--LMGQPFDKKILEELIEEVDEDKSGRLEFGEFVQLA 76
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRklEEGEPLSDEEVEELFKEFDLDKDGRISFEEFLELY 66

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        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665410492  16 LQKAFNSFDHQKTGSIPT-EMVADILRLMGQPFDKKILEELIEEVDEDKSGRLEFGEFVQLAaKFIveedaeamqKELRE 94
Cdd:cd16184    2 VQQWFQAVDRDRSGKISAkELQQALVNGNWSHFNDETCRLMIGMFDKDKSGTIDIYEFQALW-NYI---------QQWKQ 71

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 665410492  95 AFRLYDKQGNGFIPTTCLKEILKELDDQLTEQELDIMIEEIDSDGSGTVDFDEF 148
Cdd:cd16184   72 VFQQFDRDRSGSIDENELHQALSQMGYRLSPQFVQFLVSKYDPRARRSLTLDQF 125

EF-hand, calcium binding motif, found in calbindin (CB); CB, also termed calbindin D28, or D-28K, or avian-type vitamin D-dependent calcium-binding protein, is a unique intracellular calcium binding protein that functions as both a calcium sensor and buffer in eukaryotic cells, which undergoes a conformational change upon calcium binding and protects cells against insults of high intracellular calcium concentration. CB is highly expressed in brain and sensory neurons. It plays essential roles in neural functioning, altering synaptic interactions in the hippocampus, modulating calcium channel activity, calcium transients, and intrinsic neuronal firing activity. It prevents a neuronal death, as well as maintains and controls calcium homeostasis. CB also modulates the activity of proteins participating in the development of neurodegenerative disorders such as Alzheimer's disease, Huntington's disease, and bipolar disorder. Moreover, CB interacts with Ran-binding protein M, a protein known to involve in microtubule function. It also interacts with alkaline phosphatase and myo-inositol monophosphatase, as well as caspase 3, an enzyme that plays an important role in the regulation of apoptosis. CB contains six EF-hand motifs in a single globular domain, where EF-hands 1, 3, 4, 5 bind four calcium ions with high affinity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665410492  18 KAFNSFDHQKTGSIPTE----MVADILRLMGQPFDKKILEELIEEV----DEDKSGRLEFGEFVQL---AAKFIVEEDAE 86
Cdd:cd16176   89 QTWRKYDADHSGFIEADelksFLKDLLKKANKPFDESKLEEYTHTMlkmfDSNNDGKLGLTEMARLlpvQENFLLKFQGV 168

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 665410492  87 AM-QKELREAFRLYDKQGNGFIPTTCLKEILKELDDQlTEQELDI 130
Cdd:cd16176  169 KMcGKEFNKIFELYDQDGNGYIDENELDALLKDLCEK-NKKDLDI 212

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 665410492  94 EAFRLYDKQGNGFIPTTCLKEILKELddQLTEQELDIMIEEIDSDGSGTVDFDEF 148
Cdd:cd00052    3 QIFRSLDPDGDGLISGDEARPFLGKS--GLPRSVLAQIWDLADTDKDGKLDKEEF 55

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 665410492   127 ELDIMIEEIDSDGSGTVDFDEFMEMMT 153
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLK 27

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        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665410492  60 DEDKSGRLEFGEFVQLAAkfiveedaeamqkELR---EAFRLYDKQGNGFIPTTCLKEILKELDDQLTEQELDIMIEEId 136
Cdd:cd16196   51 DVDRSGKLGFEEFKKLWE-------------DLRswkRVFKLFDTDGSGSFSSFELRNALNSAGFRLSNATLNALVLRY- 116

                         90
                 ....*....|....*..
gi 665410492 137 SDGSGTVDFDEFMEMMT 153
Cdd:cd16196  117 SNKDGRISFDDFIMCAV 133

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 665410492  17 QKAFNSFDHQKTGSIPTEMVADILRLMGQPfdKKILEELIEEVDEDKSGRLEFGEFV 73
Cdd:cd00052    2 DQIFRSLDPDGDGLISGDEARPFLGKSGLP--RSVLAQIWDLADTDKDGKLDKEEFA 56

EF-hand, calcium binding motif, found in CREC-EF hand family; The CREC (Cab45/reticulocalbin/ERC45/calumenin)-EF hand family contains a group of six EF-hand, low-affinity Ca2+-binding proteins, including reticulocalbin (RCN-1), ER Ca2+-binding protein of 55 kDa (ERC-55, also known as TCBP-49 or E6BP), reticulocalbin-3 (RCN-3), Ca2+-binding protein of 45 kDa (Cab45 and its splice variant Cab45b), and calumenin ( also known as crocalbin or CBP-50). The proteins are not only localized in various parts of the secretory pathway, but also found in the cytosolic compartment and at the cell surface. They interact with different ligands or proteins and have been implicated in the secretory process, chaperone activity, signal transduction as well as in a large variety of disease processes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665410492  51 ILEELIEEVDEDKSGRLEFGEFVQLAAKFIVEEDAEAMQKELREAFR-LYDKQGNGFIPTTCLKEILKELDDQLTEQELD 129
Cdd:cd15899  161 VIKETLEDLDKNGDGFISLEEFISDPYSADENEEEPEWVKVEKERFVeLRDKDKDGKLDGEELLSWVDPSNQEIALEEAK 240

                         90       100
                 ....*....|....*....|.
gi 665410492 130 IMIEEIDSDGSGTVDFDEFME 150
Cdd:cd15899  241 HLIAESDENKDGKLSPEEILD 261

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 665410492  45 QPFDKKILEELIEEVDEDKSGRLEFGEFVQLAAKFiveedaeamqKELREAFRLYDKQGNGFIPTTCLKEILKELDDQLT 124
Cdd:cd16181   35 QPFSLETCRLMIAMLDRDHSGKMGFNEFKELWAAL----------NQWKTTFMQYDRDRSGTVEPQELQQAIRSFGYNLS 104

                         90       100
                 ....*....|....*....|....
gi 665410492 125 EQELDIMIEEIDSDGSGTvdFDEF 148
Cdd:cd16181  105 PQALNVIVKRYSKNGRIT--FDDF 126