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 1039770201   1 MSGTMGFNEFKELWAVLNGWRQHFISFDSDRSGTVDPQELQKALTTMGFRLSPQTVNSVAKRYSTSGKITFDDYIACCVK 80
Cdd:cd16187    53 MSGTMGFNEFKELWAVLNGWRQHFISFDSDRSGTVDPQELQKALTTMGFRLSPQAVNSIAKRYSTNGKITFDDYIACCVK 132

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1039770201  81 LRALTDSFRRRDSGQQGVVNFSYDDFIQCVMTV 113
Cdd:cd16187   133 LRALTDSFRRRDTSQQGVVNFPYDDFIQCVMSI 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 1039770201   1 MSGTMGFNEFKELWAVLNGWRQHFISFDSDRSGTVDPQELQKALTTMGFRLSPQTVNSVAKRYSTSGKITFDDYIACCVK 80
Cdd:cd16187    53 MSGTMGFNEFKELWAVLNGWRQHFISFDSDRSGTVDPQELQKALTTMGFRLSPQAVNSIAKRYSTNGKITFDDYIACCVK 132

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1039770201  81 LRALTDSFRRRDSGQQGVVNFSYDDFIQCVMTV 113
Cdd:cd16187   133 LRALTDSFRRRDTSQQGVVNFPYDDFIQCVMSI 165

centrin; Provisional

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1039770201  21 RQHFISFDSDRSGTVDPQELQKALTTMGFRLSPQTVNSVAKRYST--SGKITFDDYiaccvkLRALTDSFRRRDS 93
Cdd:PTZ00183   20 REAFDLFDTDGSGTIDPKELKVAMRSLGFEPKKEEIKQMIADVDKdgSGKIDFEEF------LDIMTKKLGERDP 88

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 1039770201   1 MSGTMGFNEFKELWAVLNGWRQHFISFDSDRSGTVDPQELQKALTTMGFRLSPQTVNSVAKRYSTSGKITFDDYIACCVK 80
Cdd:cd16187    53 MSGTMGFNEFKELWAVLNGWRQHFISFDSDRSGTVDPQELQKALTTMGFRLSPQAVNSIAKRYSTNGKITFDDYIACCVK 132

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1039770201  81 LRALTDSFRRRDSGQQGVVNFSYDDFIQCVMTV 113
Cdd:cd16187   133 LRALTDSFRRRDTSQQGVVNFPYDDFIQCVMSI 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 1039770201   1 MSGTMGFNEFKELWAVLNGWRQHFISFDSDRSGTVDPQELQKALTTMGFRLSPQTVNSVAKRYSTSGKITFDDYIACCVK 80
Cdd:cd16186    53 HTGKMGFNEFKELWAALNAWKQNFMTVDQDRSGTVEPHELRQAIGAMGYRLSPQTLTTIVKRYSKNGRIYFDDYVACCVK 132

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1039770201  81 LRALTDSFRRRDSGQQGVVNFSYDDFIQCVMTV 113
Cdd:cd16186   133 LRALTDFFRRRDHMQQGSVNFIYDDFLQCTMAI 165

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 1039770201   2 SGTMGFNEFKELWAVLNGWRQHFISFDSDRSGTVDPQELQKALTTMGFRLSPQTVNSVAKRYS-TSGKITFDDYIACCVK 80
Cdd:cd15897    54 SGKLNFSEFKGLWNYIKAWQEIFRTYDTDGSGTIDSNELRQALSGAGYRLSEQTYDIIIRRYDrGRGNIDFDDFIQCCVR 133

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1039770201  81 LRALTDSFRRRDSGQQGVVNFSYDDFIQCVM 111
Cdd:cd15897   134 LQRLTDAFRRYDKDQDGQIQVNYDEFLQGTM 164

EF-hand, calcium binding motif, found in apoptosis-linked gene 2 protein (ALG-2) and similar proteins; ALG-2, also termed programmed cell death protein 6 (PDCD6), or probable calcium-binding protein ALG-2, is one of the prototypic members of the penta EF-hand protein family. It is a widely expressed calcium-binding modulator protein associated with cell proliferation and death, as well as cell survival. ALG-2 acts as a pro-apoptotic factor participating in T cell receptor-, Fas-, and glucocorticoid-induced programmed cell death, and also serves as a useful molecular marker for the prognosis of cancers. Moreover, ALG-2 functions as a calcium ion sensor at endoplasmic reticulum (ER) exit sites, and modulates ER-stress-stimulated cell death and neuronal apoptosis during organ formation. Furthermore, ALG-2 can mediate the pro-apoptotic activity of cisplatin or tumor necrosis factor alpha (TNFalpha) through the down-regulation of nuclear factor-kappaB (NF-kappaB) expression. It also inhibits angiogenesis through PI3K/mTOR/p70S6K pathway by interacting of vascular endothelial growth factor receptor-2 (VEGFR-2). In addition, nuclear ALG-2 may participate in the post-transcriptional regulation of Inositol Trisphosphate Receptor Type 1 (IP3R1) pre-mRNA at least in part by interacting with CHERP (Ca2+ homeostasis endoplasmic reticulum protein) calcium-dependently. ALG-2 contains five serially repeated EF-hand motifs and interacts with various proteins, including ALG-2-interacting protein X (Alix), Fas, annexin XI, death-associated protein kinase 1 (DAPk1), Tumor susceptibility gene 101 (TSG101), Sec31A, phospholipid scramblase 3 (PLSCR3), the P-body component PATL1, and endosomal sorting complex required for transport (ESCRT)-III-related protein IST1, in a calcium-dependent manner. It forms a homodimer in the cell or a heterodimer with its closest paralog peflin. Among the PEF proteins, ALG-2 can bind three Ca2+ ions through its EF1, EF3, and EF5 hands, where it is unique in that its EF5 hand binds Ca2+ ion in a canonical coordination.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039770201   2 SGTMGFNEFKELWAVLNGWRQHFISFDSDRSGTVDPQELQKALTTMGFRLSPQTVNSVAKRYSTSGK--ITFDDYIACCV 79
Cdd:cd16183    51 SGTINFQEFAALWKYITDWQNCFRSFDRDNSGNIDKNELKQALTSFGYRLSDQFYDILVRKFDRQGRgtIAFDDFIQCCV 130

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1039770201  80 KLRALTDSFRRRDSGQQGVVNFSYDDFIQCV 110
Cdd:cd16183   131 VLQTLTDSFRRYDTDQDGWIQISYEQFLEMV 161

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 1039770201   1 MSGTMGFNEFKELWAVLNGWRQHFISFDSDRSGTVDPQELQKALTTMGFRLSPQTVNSVAKRYST-SGKITFDDYIACCV 79
Cdd:cd16196    54 RSGKLGFEEFKKLWEDLRSWKRVFKLFDTDGSGSFSSFELRNALNSAGFRLSNATLNALVLRYSNkDGRISFDDFIMCAV 133

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1039770201  80 KLRALTDSFRRRDSGQQGVVNFSYDDFIQCVMT 112
Cdd:cd16196   134 KLKTMFEIFKEKDPRGGGRATFNLDEFLESTMY 166

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 1039770201   2 SGTMGFNEFKELWAVLNGWRQHFISFDSDRSGTVDPQELQKALTTMGFRLSPQTVNSVAKRYST-SGKITFDDYIACCVK 80
Cdd:cd16188    57 TGKLGFEEFKYLWNNIKKWQGIYKQFDTDRSGTIGSQELPGAFEAAGFHLNEQLYQMIIRRYSDeDGNMDFDNFISCLVR 136

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1039770201  81 LRALTDSFRRRDSGQQGVVNFSYDDFIQCVM 111
Cdd:cd16188   137 LDAMFRAFKSLDKDGTGQIQVNIQEWLQLTM 167

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 1039770201   2 SGTMGFNEFKELWAVLNGWRQHFISFDSDRSGTVDPQELQKALTTMGFRLSPQTVNSVAKRYSTSG-KITFDDYIACCVK 80
Cdd:cd16191    57 TGTLGLVEFRILWMKIQKYLAIYKKVDSDRSGTIDAHEMRNALQEAGFTLNNKIQQSIVQRYASNKlTINFDGFIACMIR 136

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1039770201  81 LRALTDSFRRRDSGQQGVVNFSYDDFIQCVM 111
Cdd:cd16191   137 LETLFKMFQLLDKDKSGVVQLSLAEWLCCTL 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 1039770201   2 SGTMGFNEFKELWAVLNGWRQHFISFDSDRSGTVDPQELQKALTTMGFRLSPQTVNSVAKRYSTSG-KITFDDYIACCVK 80
Cdd:cd16194    57 NGKLALEEFQQLWGYLLEWQAIFTKFDEDTSGTMDSYELRLALNAAGFHLNNQLTETLTSRYRDSRlRVDFESFLSCLAH 136

                          90       100
                  ....*....|....*....|....*...
gi 1039770201  81 LRALTDSFRRRDSGQQGVVNFSYDDFIQ 108
Cdd:cd16194   137 LTCIFCQCSQHDDGGEGVICLTHRQWLE 164

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 1039770201   2 SGTMGFNEFKELWAVLNGWRQHFISFDSDRSGTVDPQELQKALTTMGFRLSPQTVNSVAKRYSTSGK-ITFDDYIACCVK 80
Cdd:cd16198    57 NGKLGLVEFNILWNKIRNYLTIFRKFDLDKSGSMSAYEMRLALESAGFKLNNRLHQVIVARYADPNLaIDFDNFVCCLVR 136

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1039770201  81 LRALTDSFRRRDSGQQGVVNFSYDDFIQCVM 111
Cdd:cd16198   137 LETMFRFFKQLDTEETGTIEMDLFEWLQLTM 167

Penta-EF hand, calcium binding motifs, found in calpain-11 (CAPN11); CAPN11, also termed calcium-activated neutral proteinase 11 (CANP 11), is a mammalian orthologue of micro/m calpain. It is one of the calpain large subunits that appears to be exclusively expressed in certain cells of the testis. It may be involved in regulating calcium-dependent signal transduction events during meiosis and sperm functional processes. CAPN11 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 1039770201   2 SGTMGFNEFKELWAVLNGWRQHFISFDSDRSGTVDPQELQKALTTMGFRLSPQTVNSVAKRYSTSGKIT-FDDYIACCVK 80
Cdd:cd16193    57 SGKLGLHEFKILWKKIKKWMEIFKECDQDRSGNLNSYEMRLAIEKAGIKMNNRVTEVVVARYADDNMIVdFDSFINCFLR 136

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1039770201  81 LRALTDSFRRRDSGQQGVVNFSYDDFIQCVM 111
Cdd:cd16193   137 LKAMFAFFLSMDTKKTGSICLSINQWLQITM 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 1039770201   2 SGTMGFNEFKELWAVLNGWRQHFISFDSDRSGTVDPQELQKALTTMGFRLSPQTVNSVAKRY-STSGKITFDDYIACCVK 80
Cdd:cd16197    55 LGRLKFQDFKDFMCSLKWWQGVFKMHTKEKTGILRAERLRDALEDVGFQLNTDVLSILILRYmRKDGTLRFGDFVSAVLH 134

                          90       100       110
                  ....*....|....*....|....*....|..
gi 1039770201  81 LRALTDSFRRRDSGQQGVVNFSYDDFIQCVMT 112
Cdd:cd16197   135 LTAAFGSFEKKDPLQNGFIKLSLTEWLKSCLM 166

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 1039770201   2 SGTMGFNEFKELWAVLNG------WRQHFISFDSDRSGTVDPQELQKALT 45
Cdd:cd00051    14 DGTISADELKAALKSLGEglseeeIDEMIREVDKDGDGKIDFEEFLELMA 63

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039770201  21 RQHFISFDSDRSGTVDPQELQKALTT--MGFRLSPQTVNSVAKRYST--SGKITFDDYIA 76
Cdd:pfam13499   5 KEAFKLLDSDGDGYLDVEELKKLLRKleEGEPLSDEEVEELFKEFDLdkDGRISFEEFLE 64

EF-hand domain;

                          10        20
                  ....*....|....*....|....*....
gi 1039770201  20 WRQHFISFDSDRSGTVDPQELQKALTTMG 48
Cdd:pfam13405   2 LREAFKLFDKDGDGKISLEELRKALRSLG 30

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039770201   9 EFKELWAVLngWRQHFISFDSDRSGTVDPQELQKALTTMGFRLSPQTVNSVAKRYST--SGKITFDDYIACCVKLR---- 82
Cdd:COG5126    26 DFEALFRRL--WATLFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDLLDTdgDGKISADEFRRLLTALGvsee 103

                          90       100
                  ....*....|....*....|....*.
gi 1039770201  83 ALTDSFRRRDSGQQGVVnfSYDDFIQ 108
Cdd:COG5126   104 EADELFARLDTDGDGKI--SFEEFVA 127