Penta-EF hand, calcium binding motifs, found in sorcin; 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. The up-regulation of sorcin is correlated with a number of cancer types, including colorectal, gastric and breast cancer. It may represent a therapeutic target for reversing tumor multidrug resistance (MDR). Sorcin participates in the regulation of calcium homeostasis in cells and is necessary for the activation of mitosis and cytokinesis. It enhances metastasis and promotes epithelial-to-mesenchymal transition of colorectal cancer. Moreover, sorcin has been implicated in the regulation of intracellular Ca2+ cycling and cardiac excitation-contraction coupling. It displays the anti-apoptotic properties via the modulation of mitochondrial Ca2+ handling in cardiac myocytes. It can target and activate the sarcolemmal Na+/Ca2+ exchanger (NCX1) in cardiac muscle. Meanwhile, sorcin modulates cardiac L-type Ca2+ current by functional interaction with the alpha1C subunit. It also associates with calcium/calmodulin-dependent protein kinase IIdeltaC (CaMKIIdelta(C)) and further modulates ryanodine receptor (RyR) function in cardiac myocytes. Furthermore, sorcin may act as a Ca2+ sensor for glucose-induced nuclear translocation and the activation of carbohydrate-responsive element-binding protein (ChREBP)-dependent genes. As a mitochondrial chaperone TRAP1 interactor, sorcin involves in mitochondrial metabolism through the TRAP1 pathway. In addition, sorcin may regulate the inhibition of type I interferon response in cells through interacting with foot-and-mouth disease virus (FMDV) VP1. Sorcin 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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189491879  34 PLYGYFAAVAGQDGQIDADELQRCLTQSGIAGGYKPFNLETCRLMVSMLDRDMSGTMGFSEFRELWTVLSGWRQHFISFD 113
Cdd:cd16187    1 PLYGYFAAVAGQDGQIDADELQRCLTQSGIAGGYKPFNLETCRLMISMLDRDMSGTMGFNEFKELWAVLNGWRQHFISFD 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189491879 114 SDRSGTVDPQELQKALTTMGFRLSPQTVNSVAKRYSTSGKITFDDYIACCVKLRALTDSFRRRDSGQQGVVNFSYDDFIQ 193
Cdd:cd16187   81 SDRSGTVDPQELQKALTTMGFRLSPQAVNSIAKRYSTNGKITFDDYIACCVKLRALTDSFRRRDTSQQGVVNFPYDDFIQ 160

                 ....*
gi 189491879 194 CVMTV 198
Cdd:cd16187  161 CVMSI 165

Penta-EF hand, calcium binding motifs, found in sorcin; 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. The up-regulation of sorcin is correlated with a number of cancer types, including colorectal, gastric and breast cancer. It may represent a therapeutic target for reversing tumor multidrug resistance (MDR). Sorcin participates in the regulation of calcium homeostasis in cells and is necessary for the activation of mitosis and cytokinesis. It enhances metastasis and promotes epithelial-to-mesenchymal transition of colorectal cancer. Moreover, sorcin has been implicated in the regulation of intracellular Ca2+ cycling and cardiac excitation-contraction coupling. It displays the anti-apoptotic properties via the modulation of mitochondrial Ca2+ handling in cardiac myocytes. It can target and activate the sarcolemmal Na+/Ca2+ exchanger (NCX1) in cardiac muscle. Meanwhile, sorcin modulates cardiac L-type Ca2+ current by functional interaction with the alpha1C subunit. It also associates with calcium/calmodulin-dependent protein kinase IIdeltaC (CaMKIIdelta(C)) and further modulates ryanodine receptor (RyR) function in cardiac myocytes. Furthermore, sorcin may act as a Ca2+ sensor for glucose-induced nuclear translocation and the activation of carbohydrate-responsive element-binding protein (ChREBP)-dependent genes. As a mitochondrial chaperone TRAP1 interactor, sorcin involves in mitochondrial metabolism through the TRAP1 pathway. In addition, sorcin may regulate the inhibition of type I interferon response in cells through interacting with foot-and-mouth disease virus (FMDV) VP1. Sorcin 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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189491879  34 PLYGYFAAVAGQDGQIDADELQRCLTQSGIAGGYKPFNLETCRLMVSMLDRDMSGTMGFSEFRELWTVLSGWRQHFISFD 113
Cdd:cd16187    1 PLYGYFAAVAGQDGQIDADELQRCLTQSGIAGGYKPFNLETCRLMISMLDRDMSGTMGFNEFKELWAVLNGWRQHFISFD 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189491879 114 SDRSGTVDPQELQKALTTMGFRLSPQTVNSVAKRYSTSGKITFDDYIACCVKLRALTDSFRRRDSGQQGVVNFSYDDFIQ 193
Cdd:cd16187   81 SDRSGTVDPQELQKALTTMGFRLSPQAVNSIAKRYSTNGKITFDDYIACCVKLRALTDSFRRRDTSQQGVVNFPYDDFIQ 160

                 ....*
gi 189491879 194 CVMTV 198
Cdd:cd16187  161 CVMSI 165

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 189491879  106 RQHFISFDSDRSGTVDPQELQKALTT--MGFRLSPQTVNSVAKRYST--SGKITFDDYIA 161
Cdd:pfam13499   5 KEAFKLLDSDGDGYLDVEELKKLLRKleEGEPLSDEEVEELFKEFDLdkDGRISFEEFLE 64

Penta-EF hand, calcium binding motifs, found in sorcin; 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. The up-regulation of sorcin is correlated with a number of cancer types, including colorectal, gastric and breast cancer. It may represent a therapeutic target for reversing tumor multidrug resistance (MDR). Sorcin participates in the regulation of calcium homeostasis in cells and is necessary for the activation of mitosis and cytokinesis. It enhances metastasis and promotes epithelial-to-mesenchymal transition of colorectal cancer. Moreover, sorcin has been implicated in the regulation of intracellular Ca2+ cycling and cardiac excitation-contraction coupling. It displays the anti-apoptotic properties via the modulation of mitochondrial Ca2+ handling in cardiac myocytes. It can target and activate the sarcolemmal Na+/Ca2+ exchanger (NCX1) in cardiac muscle. Meanwhile, sorcin modulates cardiac L-type Ca2+ current by functional interaction with the alpha1C subunit. It also associates with calcium/calmodulin-dependent protein kinase IIdeltaC (CaMKIIdelta(C)) and further modulates ryanodine receptor (RyR) function in cardiac myocytes. Furthermore, sorcin may act as a Ca2+ sensor for glucose-induced nuclear translocation and the activation of carbohydrate-responsive element-binding protein (ChREBP)-dependent genes. As a mitochondrial chaperone TRAP1 interactor, sorcin involves in mitochondrial metabolism through the TRAP1 pathway. In addition, sorcin may regulate the inhibition of type I interferon response in cells through interacting with foot-and-mouth disease virus (FMDV) VP1. Sorcin 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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189491879  34 PLYGYFAAVAGQDGQIDADELQRCLTQSGIAGGYKPFNLETCRLMVSMLDRDMSGTMGFSEFRELWTVLSGWRQHFISFD 113
Cdd:cd16187    1 PLYGYFAAVAGQDGQIDADELQRCLTQSGIAGGYKPFNLETCRLMISMLDRDMSGTMGFNEFKELWAVLNGWRQHFISFD 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189491879 114 SDRSGTVDPQELQKALTTMGFRLSPQTVNSVAKRYSTSGKITFDDYIACCVKLRALTDSFRRRDSGQQGVVNFSYDDFIQ 193
Cdd:cd16187   81 SDRSGTVDPQELQKALTTMGFRLSPQAVNSIAKRYSTNGKITFDDYIACCVKLRALTDSFRRRDTSQQGVVNFPYDDFIQ 160

                 ....*
gi 189491879 194 CVMTV 198
Cdd:cd16187  161 CVMSI 165

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 189491879  34 PLYGYFAAVAGQDGQIDADELQRCLTQSGIAGGYKPFNLETCRLMVSMLDRDMSGTMGFSEFRELWTVLSGWRQHFISFD 113
Cdd:cd16186    1 PMWGYFSAVAGQDGEVDAEELQRCLTQSGINGTYTPFSLETCRIMIAMLDRDHTGKMGFNEFKELWAALNAWKQNFMTVD 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189491879 114 SDRSGTVDPQELQKALTTMGFRLSPQTVNSVAKRYSTSGKITFDDYIACCVKLRALTDSFRRRDSGQQGVVNFSYDDFIQ 193
Cdd:cd16186   81 QDRSGTVEPHELRQAIGAMGYRLSPQTLTTIVKRYSKNGRIYFDDYVACCVKLRALTDFFRRRDHMQQGSVNFIYDDFLQ 160

                 ....*
gi 189491879 194 CVMTV 198
Cdd:cd16186  161 CTMAI 165

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 189491879  35 LYGYFAAV-AGQDGQIDADELQRCLTQsgiaGGYKPFNLETCRLMVSMLDRDMSGTMGFSEFRELWTVLSGWRQHFISFD 113
Cdd:cd16184    2 VQQWFQAVdRDRSGKISAKELQQALVN----GNWSHFNDETCRLMIGMFDKDKSGTIDIYEFQALWNYIQQWKQVFQQFD 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189491879 114 SDRSGTVDPQELQKALTTMGFRLSPQTVNSVAKRYSTSGK--ITFDDYIACCVKLRALTDSFRRRDSGQQGVVNFSYDDF 191
Cdd:cd16184   78 RDRSGSIDENELHQALSQMGYRLSPQFVQFLVSKYDPRARrsLTLDQFIQVCVQLQSLTDAFRQRDTQMTGTITISYEDF 157

                 ....*.
gi 189491879 192 IQCVMT 197
Cdd:cd16184  158 LTMALL 163

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 189491879  47 GQIDADELQRCLTQsgiaGGYKPFNLETCRLMVSMLDRDMSGTMGFSEFRELWTVLSGWRQHFISFDSDRSGTVDPQELQ 126
Cdd:cd16180   15 GRISAKELQRALSN----GDWTPFSIETVRLMINMFDRDRSGTINFDEFVGLWKYIQDWRRLFRRFDRDRSGSIDFNELQ 90

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 189491879 127 KALTTMGFRLSPQTVNSVAKRYST--SGKITFDDYIACCVKLRALTDSFRRRDSGQQGVVNFSYDDFIQCVM 196
Cdd:cd16180   91 NALSSFGYRLSPQFVQLLVRKFDRrrRGSISFDDFVEACVTLKRLTDAFRKYDTNRTGYATISYEDFLTMVL 162

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 189491879  39 FAAVAGQDGQIDADELQRCLTQSGIAGGYKP--FNLETCRLMVSMLDRDMSGTMGFSEFRELWTVLSGWRQHFISFDSDR 116
Cdd:cd16182    6 FEKLAGEDEEIDAVELQKLLNASLLKDMPKFdgFSLETCRSLIALMDTNGSGRLDLEEFKTLWSDLKKWQAIFKKFDTDR 85

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189491879 117 SGTVDPQELQKALTTMGFRLSPQTVNSVAKRYSTS-GKITFDDYIACCVKLRALTDSFRRRDSGQQGVVNFSYDDFIQCV 195
Cdd:cd16182   86 SGTLSSYELRKALESAGFHLSNKVLQALVLRYADStGRITFEDFVSCLVRLKTAFETFSALDKKNEGVIPLTLEEWLLLT 165

                 .
gi 189491879 196 M 196
Cdd:cd16182  166 L 166

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 189491879  34 PLYGYFAAV-AGQDGQIDADELQRCLTQSGIaggykPFNLETCRLMVSMLDRDMSGTMGFSEFRELWTVLSGWRQHFISF 112
Cdd:cd16185    1 ELRQWFRAVdRDRSGSIDVNELQKALAGGGL-----LFSLATAEKLIRMFDRDGNGTIDFEEFAALHQFLSNMQNGFEQR 75

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189491879 113 DSDRSGTVDPQELQKALTTMGFRLSPQTVNSVAKRYST--SGKITFDDYIACCVKLRALTDSFRRRDSGQQGVVNFSYDD 190
Cdd:cd16185   76 DTSRSGRLDANEVHEALAASGFQLDPPAFQALFRKFDPdrGGSLGFDDYIELCIFLASARNLFQAFDRQRTGRVTLDFNQ 155

                 ....*...
gi 189491879 191 FIQCVMTV 198
Cdd:cd16185  156 FVYAAANL 163

Penta-EF hand, calcium binding motifs, found in calpain-9 (CAPN9); CAPN9, also termed digestive tract-specific calpain, or new calpain 4 (nCL-4), or protein CG36, is a calpain large subunit predominantly expressed in gastrointestinal tract. It plays a physiological role in the suppression of tumorigenesis. It acts as an important biomolecule link for the regression of colorectal cancer via intracellular calcium homeostasis. CAPN9 may also play a critical role in lumen formation. Moreover, CAPN9, together with CAPN8, forms an active protease complex, G-calpain, in which both proteins are essential for stability and activity. The G-Calpain has been implicated in gastric mucosal defense. Furthermore, down-regulation of calpain 9 has been linked to hypertensive heart and kidney disease in salt-sensitive Dahl rats. CAPN9 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 189491879  39 FAAVAGQDGQIDADELQRCLT-----QSGIAggYKPFNLETCRLMVSMLDRDMSGTMGFSEFRELWTVLSGWRQHFISFD 113
Cdd:cd16192    6 FEQISGEDLEISAEELQYVLNavlarTKEIK--FKKLSLLSCKNIISLMDTSGNGKLGFSEFKVFWDKLKKWIGLFLKYD 83

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189491879 114 SDRSGTVDPQELQKALTTMGFRLSPQTVNSVAKRYSTSG-KITFDDYIACCVKLRALTDSFRRRDSGQQGVVNFSYDDFI 192
Cdd:cd16192   84 ADRSGTMSSYELRSALKAAGFQLNNQLLQLIVLRYADDYlQIDFDDFLNCLVRLENSFRVFQALDTKNTGEISLNMLEFI 163

                 ....*.
gi 189491879 193 QCVMTV 198
Cdd:cd16192  164 LLTMNI 169

Penta-EF hand, calcium binding motifs, found in calpain-8 (CAPN8); CAPN8, also termed new calpain 2 (nCL-2), or stomach-specific M-type calpain, is a calpain large subunit predominantly expressed in the stomach. It appears to be involved in membrane trafficking in the gastric surface mucus cells (pit cells), via its location at the Golgi and interaction with the beta-subunit of coatomer complex (beta-COP) of vesicles derived from the Golgi. Moreover, CAPN8, together with CAPN9, forms an active protease complex, G-calpain, in which both proteins are essential for stability and activity. The G-Calpain has been implicated in gastric mucosal defense. CAPN8 exists as both a monomer and homo-oligomer, but not as a heterodimer with the conventional calpain regulatory subunit (30K). The monomer and homodimer forms predominate. CAPN8 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 189491879  39 FAAVAGQDGQIDADELQRCLTQsgiAGGYKP------FNLETCRLMVSMLDRDMSGTMGFSEFRELWTVLSGWRQHFISF 112
Cdd:cd16191    6 FQKLAGKKCEVTANELQTILNR---VLSKRKdiksdgFTINTCREMISLLDTDGTGTLGLVEFRILWMKIQKYLAIYKKV 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189491879 113 DSDRSGTVDPQELQKALTTMGFRLSPQTVNSVAKRYSTSG-KITFDDYIACCVKLRALTDSFRRRDSGQQGVVNFSYDDF 191
Cdd:cd16191   83 DSDRSGTIDAHEMRNALQEAGFTLNNKIQQSIVQRYASNKlTINFDGFIACMIRLETLFKMFQLLDKDKSGVVQLSLAEW 162

                 ....*
gi 189491879 192 IQCVM 196
Cdd:cd16191  163 LCCTL 167

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        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189491879  39 FAAVAGQDGQIDADELQRCLTQsgIAGGYKP-----FNLETCRLMVSMLDRDMSGTMGFSEFRELWTVLSGWRQHFISFD 113
Cdd:cd16190    6 FQQIAGDDMEISADELRSVLNR--VVKKHKDlktegFTLESCRSMIALMDTDGSGKLNLQEFRHLWNKIKQWQKIFKRYD 83

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189491879 114 SDRSGTVDPQELQKALTTMGFRLSPQTVNSVAKRYSTSG-KITFDDYIACCVKLRALTDSFRRRDSGQQGVVNFSYDDFI 192
Cdd:cd16190   84 TDKSGTINSYEMRNAVNDAGFRLNNQLYDIITMRYADKHmNIDFDSFICCFVRLEGMFRAFHAFDKDGDGIIKLNVLEWL 163

                 ....
gi 189491879 193 QCVM 196
Cdd:cd16190  164 QLTM 167

Penta-EF hand, calcium binding motifs, found in mu-type calpain (CAPN1); CAPN1, also termed calpain-1 80-kDa catalytic subunit, or calpain-1 large subunit, or micromolar-calpain (muCANP), or calcium-activated neutral proteinase 1 (CANP 1), or cell proliferation-inducing gene 30 protein, 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 CAPN1 in complex with a regulatory subunit encoded by CAPNS1 forms a mu-calpain heterodimer. CAPN1 plays a central role in postmortem proteolysis and meat tenderization processes, as well as in regulation of proliferation and survival of skeletal satellite cells. It also acts as a novel regulator in IgE-mediated mast cell activation and could serve as a potential therapeutic target for the management of allergic inflammation. Moreover, CAPN1 is involved in neutrophil motility and functions as a potential target for intervention in inflammatory disease. It also facilitates age-associated aortic wall calcification and fibrosis through the regulation of matrix metalloproteinase 2 activity in vascular smooth muscle cells, and thus plays a role in hypertension and atherosclerosis. The proteolytic cleavage of beta-amyloid precursor protein and tau protein by CAPN1 may be involved in plaque formation. Furthermore, CAPN1 is activated in the brains of individuals with Alzheimer's disease. It is involved in the maintenance of a proliferative neural stem cell pool. The activation and macrophage inflammation of CAPN1 in hypercholesterolemic nephropathy is promoted by nicotinic acetylcholine receptor alpha1 (nAChRalpha1). In addition, CAPN1 displays a functional role in hemostasis, as well as in sickle cell disease.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189491879  39 FAAVAGQDGQIDADELQRCLTQsgIAGGYKP-----FNLETCRLMVSMLDRDMSGTMGFSEFRELWTVLSGWRQHFISFD 113
Cdd:cd16198    6 FRQLAGEDMEISVFELKTILNR--IISKHKDlrtdgFSLESCRSMVNLMDKDGNGKLGLVEFNILWNKIRNYLTIFRKFD 83

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189491879 114 SDRSGTVDPQELQKALTTMGFRLSPQTVNSVAKRYSTSGK-ITFDDYIACCVKLRALTDSFRRRDSGQQGVVNFSYDDFI 192
Cdd:cd16198   84 LDKSGSMSAYEMRLALESAGFKLNNRLHQVIVARYADPNLaIDFDNFVCCLVRLETMFRFFKQLDTEETGTIEMDLFEWL 163

                 ....
gi 189491879 193 QCVM 196
Cdd:cd16198  164 QLTM 167

Penta-EF hand, calcium binding motifs, found in Drosophila melanogaster calpain-C (CalpC) and similar proteins; CalpC, also termed calcium-activated neutral proteinase homolog C (CANP C), is a catalytically inactive homolog of CalpA and CalpB found in Drosophila. It is strongly expressed in the salivary glands. In contrast with CalpA and CalpB, both of which 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. CalpC is a truncated calpain form missing domain I and about 20 residues from domain II. Moreover, due to all three mutated active site residues (Cys to Arg, His to Val and Asn to Ser), it may not have proteolytic activity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189491879  39 FAAVAGQDGQIDADELQR----CLTQSGIAGGYkpfNLETCRLMVSMLDRDMSGTMGFSEFRELWTVLSGWRQHFISFDS 114
Cdd:cd16197    6 FLQLADEHRTVNAFELQElleaCLPNDYIKSCA---NIDVCRQVVLLMDNSGLGRLKFQDFKDFMCSLKWWQGVFKMHTK 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189491879 115 DRSGTVDPQELQKALTTMGFRLSPQTVNSVAKRY-STSGKITFDDYIACCVKLRALTDSFRRRDSGQQGVVNFSYDDFIQ 193
Cdd:cd16197   83 EKTGILRAERLRDALEDVGFQLNTDVLSILILRYmRKDGTLRFGDFVSAVLHLTAAFGSFEKKDPLQNGFIKLSLTEWLK 162

                 ....
gi 189491879 194 CVMT 197
Cdd:cd16197  163 SCLM 166

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189491879  46 DGQIDADELQRcltqsgiaggykpFNLETCRLMVSMLDRDMSGTMGFSEFRELWTVLSGW------RQHFISFDSDRSGT 119
Cdd:COG5126   19 DGVLERDDFEA-------------LFRRLWATLFSEADTDGDGRISREEFVAGMESLFEAtvepfaRAAFDLLDTDGDGK 85

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 189491879 120 VDPQELQKALTTMGfrLSPQTVNSVAKRYST--SGKITFDDYIA 161
Cdd:COG5126   86 ISADEFRRLLTALG--VSEEEADELFARLDTdgDGKISFEEFVA 127

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
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 189491879  45 QDGQIDADELQRCLTQSGIaggykPFNLETCRLMVSMLDRDMSGTMGFSEFRELWT 100
Cdd:cd00051   13 GDGTISADELKAALKSLGE-----GLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 189491879  106 RQHFISFDSDRSGTVDPQELQKALTT--MGFRLSPQTVNSVAKRYST--SGKITFDDYIA 161
Cdd:pfam13499   5 KEAFKLLDSDGDGYLDVEELKKLLRKleEGEPLSDEEVEELFKEFDLdkDGRISFEEFLE 64

centrin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189491879  47 GQIDADELQRCLTqsgiAGGYKPFNlETCRLMVSMLDRDMSGTMGFSEFRELWTVLSGWR-------QHFISFDSDRSGT 119
Cdd:PTZ00183  32 GTIDPKELKVAMR----SLGFEPKK-EEIKQMIADVDKDGSGKIDFEEFLDIMTKKLGERdpreeilKAFRLFDDDKTGK 106

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 189491879 120 VDPQELQKALTTMGFRLSPQTVNSVAKRYSTS--GKITFDDYI 160
Cdd:PTZ00183 107 ISLKNLKRVAKELGETITDEELQEMIDEADRNgdGEISEEEFY 149

centrin; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 189491879 106 RQHFISFDSDRSGTVDPQELQKALTTMGFRLSPQTVNSVAKRYST--SGKITFDDYiaccvkLRALTDSFRRRDS 178
Cdd:PTZ00183  20 REAFDLFDTDGSGTIDPKELKVAMRSLGFEPKKEEIKQMIADVDKdgSGKIDFEEF------LDIMTKKLGERDP 88

EF-hand domain;

                          10        20
                  ....*....|....*....|....*....
gi 189491879  105 WRQHFISFDSDRSGTVDPQELQKALTTMG 133
Cdd:pfam13405   2 LREAFKLFDKDGDGKISLEELRKALRSLG 30