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 4507207   34 PLYGYFAAVAGQDGQIDADELQRCLTQSGIAGGYKPFNLETCRLMVSMLDRDMSGTMGFNEFKELWAVLNGWRQHFISFD 113
Cdd:cd16187   1 PLYGYFAAVAGQDGQIDADELQRCLTQSGIAGGYKPFNLETCRLMISMLDRDMSGTMGFNEFKELWAVLNGWRQHFISFD 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507207  114 TDRSGTVDPQELQKALTTMGFRLSPQAVNSIAKRYSTNGKITFDDYIACCVKLRALTDSFRRRDTAQQGVVNFPYDDFIQ 193
Cdd:cd16187  81 SDRSGTVDPQELQKALTTMGFRLSPQAVNSIAKRYSTNGKITFDDYIACCVKLRALTDSFRRRDTSQQGVVNFPYDDFIQ 160

                ....*
gi 4507207  194 CVMSV 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 4507207   34 PLYGYFAAVAGQDGQIDADELQRCLTQSGIAGGYKPFNLETCRLMVSMLDRDMSGTMGFNEFKELWAVLNGWRQHFISFD 113
Cdd:cd16187   1 PLYGYFAAVAGQDGQIDADELQRCLTQSGIAGGYKPFNLETCRLMISMLDRDMSGTMGFNEFKELWAVLNGWRQHFISFD 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507207  114 TDRSGTVDPQELQKALTTMGFRLSPQAVNSIAKRYSTNGKITFDDYIACCVKLRALTDSFRRRDTAQQGVVNFPYDDFIQ 193
Cdd:cd16187  81 SDRSGTVDPQELQKALTTMGFRLSPQAVNSIAKRYSTNGKITFDDYIACCVKLRALTDSFRRRDTSQQGVVNFPYDDFIQ 160

                ....*
gi 4507207  194 CVMSV 198
Cdd:cd16187 161 CVMSI 165

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507207    106 RQHFISFDTDRSGTVDPQELQKALTT--MGFRLSPQAVNSIAKRYSTN--GKITFDDYIA 161
Cdd:pfam13499   5 KEAFKLLDSDGDGYLDVEELKKLLRKleEGEPLSDEEVEELFKEFDLDkdGRISFEEFLE 64

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        30
                   ....*....|....*....|....*....|....*....
gi 4507207      94 EFKELWAVlngwrqhfisFDTDRSGTVDPQELQKALTTM 132
Cdd:smart00054   1 ELKEAFRL----------FDKDGDGKIDFEEFKDLLKAL 29

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 4507207   34 PLYGYFAAVAGQDGQIDADELQRCLTQSGIAGGYKPFNLETCRLMVSMLDRDMSGTMGFNEFKELWAVLNGWRQHFISFD 113
Cdd:cd16187   1 PLYGYFAAVAGQDGQIDADELQRCLTQSGIAGGYKPFNLETCRLMISMLDRDMSGTMGFNEFKELWAVLNGWRQHFISFD 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507207  114 TDRSGTVDPQELQKALTTMGFRLSPQAVNSIAKRYSTNGKITFDDYIACCVKLRALTDSFRRRDTAQQGVVNFPYDDFIQ 193
Cdd:cd16187  81 SDRSGTVDPQELQKALTTMGFRLSPQAVNSIAKRYSTNGKITFDDYIACCVKLRALTDSFRRRDTSQQGVVNFPYDDFIQ 160

                ....*
gi 4507207  194 CVMSV 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 4507207   34 PLYGYFAAVAGQDGQIDADELQRCLTQSGIAGGYKPFNLETCRLMVSMLDRDMSGTMGFNEFKELWAVLNGWRQHFISFD 113
Cdd:cd16186   1 PMWGYFSAVAGQDGEVDAEELQRCLTQSGINGTYTPFSLETCRIMIAMLDRDHTGKMGFNEFKELWAALNAWKQNFMTVD 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507207  114 TDRSGTVDPQELQKALTTMGFRLSPQAVNSIAKRYSTNGKITFDDYIACCVKLRALTDSFRRRDTAQQGVVNFPYDDFIQ 193
Cdd:cd16186  81 QDRSGTVEPHELRQAIGAMGYRLSPQTLTTIVKRYSKNGRIYFDDYVACCVKLRALTDFFRRRDHMQQGSVNFIYDDFLQ 160

                ....*
gi 4507207  194 CVMSV 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 4507207   35 LYGYFAAV-AGQDGQIDADELQRCLTQsgiaGGYKPFNLETCRLMVSMLDRDMSGTMGFNEFKELWAVLNGWRQHFISFD 113
Cdd:cd16184   2 VQQWFQAVdRDRSGKISAKELQQALVN----GNWSHFNDETCRLMIGMFDKDKSGTIDIYEFQALWNYIQQWKQVFQQFD 77

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507207  114 TDRSGTVDPQELQKALTTMGFRLSPQAVNSIAKRYST--NGKITFDDYIACCVKLRALTDSFRRRDTAQQGVVNFPYDDF 191
Cdd:cd16184  78 RDRSGSIDENELHQALSQMGYRLSPQFVQFLVSKYDPraRRSLTLDQFIQVCVQLQSLTDAFRQRDTQMTGTITISYEDF 157

                ....*.
gi 4507207  192 IQCVMS 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 4507207   47 GQIDADELQRCLTQsgiaGGYKPFNLETCRLMVSMLDRDMSGTMGFNEFKELWAVLNGWRQHFISFDTDRSGTVDPQELQ 126
Cdd:cd16180  15 GRISAKELQRALSN----GDWTPFSIETVRLMINMFDRDRSGTINFDEFVGLWKYIQDWRRLFRRFDRDRSGSIDFNELQ 90

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 4507207  127 KALTTMGFRLSPQAVNSIAKRYST--NGKITFDDYIACCVKLRALTDSFRRRDTAQQGVVNFPYDDFIQCVMSV 198
Cdd:cd16180  91 NALSSFGYRLSPQFVQLLVRKFDRrrRGSISFDDFVEACVTLKRLTDAFRKYDTNRTGYATISYEDFLTMVLSI 164

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 4507207   39 FAAVAGQDGQIDADELQRCLTQSGIAGGYKP--FNLETCRLMVSMLDRDMSGTMGFNEFKELWAVLNGWRQHFISFDTDR 116
Cdd:cd16182   6 FEKLAGEDEEIDAVELQKLLNASLLKDMPKFdgFSLETCRSLIALMDTNGSGRLDLEEFKTLWSDLKKWQAIFKKFDTDR 85

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507207  117 SGTVDPQELQKALTTMGFRLSPQAVNSIAKRYST-NGKITFDDYIACCVKLRALTDSFRRRDTAQQGVVNFPYDDFIQCV 195
Cdd:cd16182  86 SGTLSSYELRKALESAGFHLSNKVLQALVLRYADsTGRITFEDFVSCLVRLKTAFETFSALDKKNEGVIPLTLEEWLLLT 165

                .
gi 4507207  196 M 196
Cdd:cd16182 166 L 166

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 4507207   39 FAAVAGQDGQIDADELQRCLT-----QSGIAggYKPFNLETCRLMVSMLDRDMSGTMGFNEFKELWAVLNGWRQHFISFD 113
Cdd:cd16192   6 FEQISGEDLEISAEELQYVLNavlarTKEIK--FKKLSLLSCKNIISLMDTSGNGKLGFSEFKVFWDKLKKWIGLFLKYD 83

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507207  114 TDRSGTVDPQELQKALTTMGFRLSPQAVNSIAKRYSTNG-KITFDDYIACCVKLRALTDSFRRRDTAQQGVVNFPYDDFI 192
Cdd:cd16192  84 ADRSGTMSSYELRSALKAAGFQLNNQLLQLIVLRYADDYlQIDFDDFLNCLVRLENSFRVFQALDTKNTGEISLNMLEFI 163

                ....*.
gi 4507207  193 QCVMSV 198
Cdd:cd16192 164 LLTMNI 169

Penta-EF hand, calcium binding motifs, found in calcium-dependent protease small subunit CAPNS1 and CAPNS2; CAPNS1, also termed calpain small subunit 1 (CSS1), or calcium-activated neutral proteinase small subunit (CANP small subunit), or calcium-dependent protease small subunit (CDPS), or calpain regulatory subunit, is a common 28-kDa regulatory calpain subunit encoded by the calpain small 1 (Capns1, also known as Capn4) gene. It acts as a binding partner to form a heterodimer with the 80 kDa calpain large catalytic subunit and is required in maintaining the activity of calpain. CAPNS1 plays a significant role in tumor progression of human cancer, and functions as a potential therapeutic target in human hepatocellular carcinoma (HCC), nasopharyngeal carcinoma (NPC), glioma, and clear cell renal cell carcinoma (ccRCC). It may be involved in regulating migration and cell survival through binding to the SH3 domain of Ras GTPase-activating protein (RasGAP). It may also modulate Akt/FoxO3A signaling and apoptosis through PP2A. CAPNS1 contains an N-terminal glycine rich domain and a C-terminal PEF-hand domain. CAPNS2, also termed calpain small subunit 2 (CSS2), is a novel tissue-specific 30 kDa calpain small subunit that lacks two oligo-Gly stretches characteristic of the N-terminal Gly-rich domain of CAPNS1. CAPNS2 acts as a chaperone for the calpain large subunit, and appears to be the functional equivalent of CAPNS1. However, CAPNS2 binds the large subunit much more weakly than CAPNS1 and it does not undergo the autolytic conversion typical of CAPNS1.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507207   39 FAAVAGQDGQIDADELQRCLTQSgIA--GGYKP--FNLETCRLMVSMLDRDMSGTMGFNEFKELWAVLNGWRQHFISFDT 114
Cdd:cd16188   6 FVQLAGDDMEVSATELMNILNKV-VTrhPDLKTdgFGIDTCRSMVAVMDSDTTGKLGFEEFKYLWNNIKKWQGIYKQFDT 84

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507207  115 DRSGTVDPQELQKALTTMGFRLSPQAVNSIAKRYST-NGKITFDDYIACCVKLRALTDSFRRRDTAQQGVVNFPYDDFIQ 193
Cdd:cd16188  85 DRSGTIGSQELPGAFEAAGFHLNEQLYQMIIRRYSDeDGNMDFDNFISCLVRLDAMFRAFKSLDKDGTGQIQVNIQEWLQ 164

                ...
gi 4507207  194 CVM 196
Cdd:cd16188 165 LTM 167

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 4507207   39 FAAVAGQDGQIDADELQRCLTQS-GIAGGYKP--FNLETCRLMVSMLDRDMSGTMGFNEFKELWAVLNGWRQHFISFDTD 115
Cdd:cd16194   6 FQELAGEDEEINASELQKILSIAlERAHTSKPreFGLRTCRQLIQCFDHGQNGKLALEEFQQLWGYLLEWQAIFTKFDED 85

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 4507207  116 RSGTVDPQELQKALTTMGFRLSPQAVNSIAKRYSTNG-KITFDDYIACCVKLRALTDSFRRRDTAQQGVVNFPYDDFIQ 193
Cdd:cd16194  86 TSGTMDSYELRLALNAAGFHLNNQLTETLTSRYRDSRlRVDFESFLSCLAHLTCIFCQCSQHDDGGEGVICLTHRQWLE 164

Penta-EF hand, calcium binding motifs, found in m-type calpain (CAPN2); CAPN2, also termed millimolar-calpain (m-calpain), or calpain-2 catalytic subunit, or calcium-activated neutral proteinase 2 (CANP 2), or calpain large polypeptide L2, or calpain-2 large subunit, 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 CAPN2 in complex with a regulatory subunit encoded by CAPNS1 forms an m-calpain heterodimer. CAPN2 acts as the key protease responsible for N-methyl-d-aspartic acid (NMDA)-induced cytoplasmic polyadenylation element-binding protein 3 (CPEB3) degradation in neurons. It cleaves several components of the focal adhesion complex, such as FAK and talin, triggering disassembly of the complex at the rear of the cell. The stimulation of CAPN2 activity is required for Golgi antiapoptotic proteins (GAAPs) to promote cleavage of FA kinase (FAK), cell spreading, and enhanced migration. calpain 2 is also involved in the onset of glial differentiation. It regulates proliferation, survival, migration, and tumorigenesis of breast cancer cells through a PP2A-Akt-FoxO-p27(Kip1) signaling cascade. Its expression is associated with response to platinum based chemotherapy, progression-free and overall survival in ovarian cancer. Moreover, CAPN2 may play a role in fundamental mitotic functions, such as the maintenance of sister chromatid cohesion. The activation of CAPN2 plays an essential role in hippocampal synaptic plasticity and in learning and memory. In the eye, CAPN2, together with a lens-specific variant of CAPN3, is responsible for proteolytic cleavages of alpha and beta-crystallin. Overactivated alpha and beta-crystallin can lead to cataract formation. Sometimes, CAPN2 compensates for loss of CAPN1, and both calpain isoforms are involved in AngII-induced aortic aneurysm formation. The main phosphorylation sites in m-calpain are Ser50 and Ser369/Thr370.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507207   39 FAAVAGQDGQIDADELQRCLtQSGIAG----GYKPFNLETCRLMVSMLDRDMSGTMGFNEFKELWAVLNGWRQHFISFDT 114
Cdd:cd16199   6 FAQLAGEDAEISAFELQTIL-RRVLAKrediKSDGFSIETCKIMVDMLDSDGSGKLGLKEFYILWTKIQKYQKIYREIDV 84

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 4507207  115 DRSGTVDPQELQKALTTMGFRLSPQAVNSIAKRYSTNGK-ITFDDYIACCVKLRALTDSFRRRDTAQQGVVNFPYDDFI 192
Cdd:cd16199  85 DRSGTMNSYEMRKALEEAGFKLPCQLHQVIVARFADDDLiIDFDNFVRCLVRLETLFKIFKQLDPENTGTIELDLISWL 163

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 4507207   39 FAAVAGQDGQIDADELQRCLTQsgIAGGYKP-----FNLETCRLMVSMLDRDMSGTMGFNEFKELWAVLNGWRQHFISFD 113
Cdd:cd16190   6 FQQIAGDDMEISADELRSVLNR--VVKKHKDlktegFTLESCRSMIALMDTDGSGKLNLQEFRHLWNKIKQWQKIFKRYD 83

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507207  114 TDRSGTVDPQELQKALTTMGFRLSPQAVNSIAKRYST-NGKITFDDYIACCVKLRALTDSFRRRDTAQQGVVNFPYDDFI 192
Cdd:cd16190  84 TDKSGTINSYEMRNAVNDAGFRLNNQLYDIITMRYADkHMNIDFDSFICCFVRLEGMFRAFHAFDKDGDGIIKLNVLEWL 163

                ....
gi 4507207  193 QCVM 196
Cdd:cd16190 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 4507207   39 FAAVAGQDGQIDADELQR----CLTQSGIAGGYkpfNLETCRLMVSMLDRDMSGTMGFNEFKELWAVLNGWRQHFISFDT 114
Cdd:cd16197   6 FLQLADEHRTVNAFELQElleaCLPNDYIKSCA---NIDVCRQVVLLMDNSGLGRLKFQDFKDFMCSLKWWQGVFKMHTK 82

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507207  115 DRSGTVDPQELQKALTTMGFRLSPQAVNSIAKRY-STNGKITFDDYIACCVKLRALTDSFRRRDTAQQGVVNFPYDDFIQ 193
Cdd:cd16197  83 EKTGILRAERLRDALEDVGFQLNTDVLSILILRYmRKDGTLRFGDFVSAVLHLTAAFGSFEKKDPLQNGFIKLSLTEWLK 162

                ....
gi 4507207  194 CVMS 197
Cdd:cd16197 163 SCLM 166

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507207   46 DGQIDADELQRcltqsgiaggykpFNLETCRLMVSMLDRDMSGTMGFNEFKELWAVLNGW------RQHFISFDTDRSGT 119
Cdd:COG5126  19 DGVLERDDFEA-------------LFRRLWATLFSEADTDGDGRISREEFVAGMESLFEAtvepfaRAAFDLLDTDGDGK 85

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....
gi 4507207  120 VDPQELQKALTTMGfrLSPQAVNSIAKRYSTN--GKITFDDYIA 161
Cdd:COG5126  86 ISADEFRRLLTALG--VSEEEADELFARLDTDgdGKISFEEFVA 127

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507207    106 RQHFISFDTDRSGTVDPQELQKALTT--MGFRLSPQAVNSIAKRYSTN--GKITFDDYIA 161
Cdd:pfam13499   5 KEAFKLLDSDGDGYLDVEELKKLLRKleEGEPLSDEEVEELFKEFDLDkdGRISFEEFLE 64

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507207    78 MVSMLDRDMSGTMGFNEFKELWA-------VLNGWRQHFISFDTDRSGTVDPQELQKALTTMGFRLSPQAVNSIAKRYST 150
Cdd:PTZ00184  52 MINEVDADGNGTIDFPEFLTLMArkmkdtdSEEEIKEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADV 131

                         90
                 ....*....|..
gi 4507207   151 NG--KITFDDYI 160
Cdd:PTZ00184 132 DGdgQINYEEFV 143

centrin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507207    47 GQIDADELQRCLTqsgiAGGYKPFNlETCRLMVSMLDRDMSGTMGFNEFKELWAVLNGWR-------QHFISFDTDRSGT 119
Cdd:PTZ00183  32 GTIDPKELKVAMR----SLGFEPKK-EEIKQMIADVDKDGSGKIDFEEFLDIMTKKLGERdpreeilKAFRLFDDDKTGK 106

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 4507207   120 VDPQELQKALTTMGFRLSPQAVNSIAKRYSTN--GKITFDDYI 160
Cdd:PTZ00183 107 ISLKNLKRVAKELGETITDEELQEMIDEADRNgdGEISEEEFY 149

EF-hand domain pair;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 4507207     45 QDGQIDADELQRCLTqsgiAGGYKPFNLETCRLMVSMLDRDMSGTMGFNEFKELW 99
Cdd:pfam13833   1 EKGVITREELKRALA----LLGLKDLSEDEVDILFREFDTDGDGYISFDEFCVLL 51

EF-hand domain pair;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 4507207     45 QDGQIDADELQRCLTQSGIAggyKPFNLETCRLMVSMLDRDMSGTMGFNEFKELW 99
Cdd:pfam13499  15 GDGYLDVEELKKLLRKLEEG---EPLSDEEVEELFKEFDLDKDGRISFEEFLELY 66

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        30
                   ....*....|....*....|....*....|....*....
gi 4507207      94 EFKELWAVlngwrqhfisFDTDRSGTVDPQELQKALTTM 132
Cdd:smart00054   1 ELKEAFRL----------FDKDGDGKIDFEEFKDLLKAL 29