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 826307938 561 QFRNIFKQIAGDDMEICADELKNVLNTVVNKHKDLKSQGFTLESCRSMIALMDTDGSGRLNLQEFHHLWKKIKAWQKIFK 640
Cdd:cd16190    1 QFRNIFQQIAGDDMEISADELRSVLNRVVKKHKDLKTEGFTLESCRSMIALMDTDGSGKLNLQEFRHLWNKIKQWQKIFK 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 826307938 641 HYDTDQSGTINSYEMRNAVNDAGFHLNSQLYDIITMRYADRHMNIDFDSFICCFIRLEGMFRAFNAFDKDGDGIIKLNVL 720
Cdd:cd16190   81 RYDTDKSGTINSYEMRNAVNDAGFRLNNQLYDIITMRYADKHMNIDFDSFICCFVRLEGMFRAFHAFDKDGDGIIKLNVL 160

                 ....*....
gi 826307938 721 EWLQLTMYA 729
Cdd:cd16190  161 EWLQLTMYA 169

Calpain-like thiol protease family; Calpain-like thiol protease family (peptidase family C2). Calcium activated neutral protease (large subunit).

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 826307938    61 FEQLHKKCLEKKVLYVDPEFPPDETSLFYSQKFPIQFVWKRPPEICENPRFIIGGANRTDICQGDLGDCWFLAAIACLTL 140
Cdd:smart00230   1 YEALRQYCKESGTLFEDPLFPANNGSLFFSQRQRKFVVWKRPHEIFENPPFIVGGASRTDICQGVLGDCWLLAALASLTL 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 826307938   141 NKRLLFRVIPHDQSFVENYAGIFHFQFWRYGDWVDVVIDDCLPTYNNQLVFTKSNHRNEFWSALLEKAYAKLHGSYEALK 220
Cdd:smart00230  81 REKLLDRVIPHDQEFSENYAGIFHFRFWRFGKWVDVVIDDRLPTYNGELVFMHSNSRNEFWSALLEKAYAKLNGCYEALK 160

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 826307938   221 GGNTTEAMEDFTGGVTEFFEIRDA---PSDMYKIMKKAIERGSLMGCSIDTIVPVQYETRMACGLVKGHAYSVTGLEETL 297
Cdd:smart00230 161 GGSTTEALEDLTGGVAESIDLKEAskdPDNLFEDLFKAFERGSLMGCSIGAGTAVEEEEQKDCGLVKGHAYSVTDVREVQ 240

                          250       260       270       280       290       300       310       320
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 826307938   298 FKdeKVKLVRLRNPWGQVEWNGSWSDGWKDWSFVDKDEKARLQHQVTEDGEFWMSYDDFIYHFTKLEICNLTADALESDK 377
Cdd:smart00230 241 GR--RQELLRLRNPWGQVEWNGPWSDDSPEWRSVSASEKKNLGLTFDDDGEFWMSFEDFLRHFDKVEICNLNPDSLEERS 318

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 826307938 561 QFRNIFKQIAGDDMEICADELKNVLNTVVNKHKDLKSQGFTLESCRSMIALMDTDGSGRLNLQEFHHLWKKIKAWQKIFK 640
Cdd:cd16190    1 QFRNIFQQIAGDDMEISADELRSVLNRVVKKHKDLKTEGFTLESCRSMIALMDTDGSGKLNLQEFRHLWNKIKQWQKIFK 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 826307938 641 HYDTDQSGTINSYEMRNAVNDAGFHLNSQLYDIITMRYADRHMNIDFDSFICCFIRLEGMFRAFNAFDKDGDGIIKLNVL 720
Cdd:cd16190   81 RYDTDKSGTINSYEMRNAVNDAGFRLNNQLYDIITMRYADKHMNIDFDSFICCFVRLEGMFRAFHAFDKDGDGIIKLNVL 160

                 ....*....
gi 826307938 721 EWLQLTMYA 729
Cdd:cd16190  161 EWLQLTMYA 169

Calpain, subdomain III. Calpains are calcium-activated cytoplasmic cysteine proteinases, participate in cytoskeletal remodeling processes, cell differentiation, apoptosis and signal transduction. Catalytic domain and the two calmodulin-like domains are separated by C2-like domain III. Domain III plays an important role in calcium-induced activation of calpain involving electrostatic interactions with subdomain II. Proposed to mediate calpain's interaction with phospholipids and translocation to cytoplasmic/nuclear membranes. CD includes subdomain III of typical and atypical calpains.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 826307938 379 QTWTVSVNEGRWVRGCSAGGCRNFPDTFWTNPQYRLKLLEEDDDPddseVICSFLVALMQKNRRKDRKLGANLFTIGFAI 458
Cdd:cd00214    1 RKWHTKSFNGEWRRGQTAGGCRNNPDTFWTNPQFRIRVPEPDDDE----GKCTVLIALMQKNRRHLRKKGLDLLTIGFHV 76

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 826307938 459 YEVPKEMHgnkqHLQKDFFLYNASKARSKTYINMREVSQRFRLPPSEYVIVPSTYEPHQEGEFILRVFSEKRNLSEE 535
Cdd:cd00214   77 YKVPGENR----HLRRDFFLHKAPRARSSTFINTREVSLRFRLPPGEYVIVPSTFEPGEEGEFLLRVFSEKSIKSSE 149

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

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 826307938 606 RSMIALMDTDGSGRLNLQEFHHLWKKIKAW----QKIFKHYDTDQSGTINSYEMRNAVND 661
Cdd:COG5126   72 RAAFDLLDTDGDGKISADEFRRLLTALGVSeeeaDELFARLDTDGDGKISFEEFVAAVRD 131

EF-hand domain;

                          10        20
                  ....*....|....*....|....*....
gi 826307938  635 WQKIFKHYDTDQSGTINSYEMRNAVNDAG 663
Cdd:pfam13405   2 LREAFKLFDKDGDGKISLEELRKALRSLG 30

Calpain-like thiol protease family; Calpain-like thiol protease family (peptidase family C2). Calcium activated neutral protease (large subunit).

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 826307938    61 FEQLHKKCLEKKVLYVDPEFPPDETSLFYSQKFPIQFVWKRPPEICENPRFIIGGANRTDICQGDLGDCWFLAAIACLTL 140
Cdd:smart00230   1 YEALRQYCKESGTLFEDPLFPANNGSLFFSQRQRKFVVWKRPHEIFENPPFIVGGASRTDICQGVLGDCWLLAALASLTL 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 826307938   141 NKRLLFRVIPHDQSFVENYAGIFHFQFWRYGDWVDVVIDDCLPTYNNQLVFTKSNHRNEFWSALLEKAYAKLHGSYEALK 220
Cdd:smart00230  81 REKLLDRVIPHDQEFSENYAGIFHFRFWRFGKWVDVVIDDRLPTYNGELVFMHSNSRNEFWSALLEKAYAKLNGCYEALK 160

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 826307938   221 GGNTTEAMEDFTGGVTEFFEIRDA---PSDMYKIMKKAIERGSLMGCSIDTIVPVQYETRMACGLVKGHAYSVTGLEETL 297
Cdd:smart00230 161 GGSTTEALEDLTGGVAESIDLKEAskdPDNLFEDLFKAFERGSLMGCSIGAGTAVEEEEQKDCGLVKGHAYSVTDVREVQ 240

                          250       260       270       280       290       300       310       320
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 826307938   298 FKdeKVKLVRLRNPWGQVEWNGSWSDGWKDWSFVDKDEKARLQHQVTEDGEFWMSYDDFIYHFTKLEICNLTADALESDK 377
Cdd:smart00230 241 GR--RQELLRLRNPWGQVEWNGPWSDDSPEWRSVSASEKKNLGLTFDDDGEFWMSFEDFLRHFDKVEICNLNPDSLEERS 318

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 826307938 561 QFRNIFKQIAGDDMEICADELKNVLNTVVNKHKDLKSQGFTLESCRSMIALMDTDGSGRLNLQEFHHLWKKIKAWQKIFK 640
Cdd:cd16190    1 QFRNIFQQIAGDDMEISADELRSVLNRVVKKHKDLKTEGFTLESCRSMIALMDTDGSGKLNLQEFRHLWNKIKQWQKIFK 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 826307938 641 HYDTDQSGTINSYEMRNAVNDAGFHLNSQLYDIITMRYADRHMNIDFDSFICCFIRLEGMFRAFNAFDKDGDGIIKLNVL 720
Cdd:cd16190   81 RYDTDKSGTINSYEMRNAVNDAGFRLNNQLYDIITMRYADKHMNIDFDSFICCFVRLEGMFRAFHAFDKDGDGIIKLNVL 160

                 ....*....
gi 826307938 721 EWLQLTMYA 729
Cdd:cd16190  161 EWLQLTMYA 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 826307938 561 QFRNIFKQIAGDDMEICADELKNVLNTVVNKHKDLKSQGFTLESCRSMIALMDTDGSGRLNLQEFHHLWKKIKAWQKIFK 640
Cdd:cd16188    1 QFRRLFVQLAGDDMEVSATELMNILNKVVTRHPDLKTDGFGIDTCRSMVAVMDSDTTGKLGFEEFKYLWNNIKKWQGIYK 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 826307938 641 HYDTDQSGTINSYEMRNAVNDAGFHLNSQLYDIITMRYADRHMNIDFDSFICCFIRLEGMFRAFNAFDKDGDGIIKLNVL 720
Cdd:cd16188   81 QFDTDRSGTIGSQELPGAFEAAGFHLNEQLYQMIIRRYSDEDGNMDFDNFISCLVRLDAMFRAFKSLDKDGTGQIQVNIQ 160

                 ....*....
gi 826307938 721 EWLQLTMYA 729
Cdd:cd16188  161 EWLQLTMYS 169

Penta-EF hand, calcium binding motifs, found in mu-type calpain (CAPN1), m-type calpain (CAPN2), and similar proteins; The family includes mu-type calpain (CAPN1) and m-type calpain (CAPN2), both of which are ubiquitously expressed 80-kDa Ca2+-dependent intracellular cysteine proteases that 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 catalytic subunit CAPN1 or CAPN2 in complex with a regulatory subunit encoded by CAPNS1 forms a mu- or m-calpain heterodimer, respectively.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 826307938 562 FRNIFKQIAGDDMEICADELKNVLNTVVNKHKDLKSQGFTLESCRSMIALMDTDGSGRLNLQEFHHLWKKIKAWQKIFKH 641
Cdd:cd16189    2 FRNLFTQLAGEDSEISAFELQTILNKVLSKRKDIKTDGFSLETCRNMVNLLDKDGSGKLGLVEFQILWTKIQKYLKIYKK 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 826307938 642 YDTDQSGTINSYEMRNAVNDAGFHLNSQLYDIITMRYADRHMNIDFDSFICCFIRLEGMFRAFNAFDKDGDGIIKLNVLE 721
Cdd:cd16189   82 FDTDGSGTMSSYEMRLALEEAGFKLNNQLHQVLVARYADQELTIDFDNFVRCLVRLELLFKIFKQLDKDNTGTIELDLIQ 161

                 ....*.
gi 826307938 722 WLQLTM 727
Cdd:cd16189  162 WLSFSL 167

Calpain large subunit, domain III; The function of the domain III and I are currently unknown. Domain II is a cysteine protease and domain IV is a calcium binding domain. Calpains are believed to participate in intracellular signaling pathways mediated by calcium ions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 826307938  387 EGRWVRGCSAGGCRNFPDTFWTNPQYRLKLLEEDDDPDDSEviCSFLVALMQKNRRKDRKLGANLFTIGFAIYEVPKEmh 466
Cdd:pfam01067   2 EGRWVRGSTAGGCRNYPDTFWTNPQYRFTLTEPDDDDDEGE--CTVLVSLMQKNRRKQRRLGENLLTIGFAIYKVPVE-- 77

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 826307938  467 gNKQHLQKDFFLYNASKARSKTYINMREVSQRFRLPPSEYVIVPSTYEPHQEGEFILRVF 526
Cdd:pfam01067  78 -LNRKLRKHFFLTNQPVARSSTYINSREVSLRFRLPPGEYVIVPSTFEPNEEGEFLLRVF 136

calpain_III domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 826307938   381 WTVSVNEGRWVRGCSAGGCRNFPDTFWTNPQYRLKLLEEDDDPddseviCSFLVALMQKNRRKDRKLGANLFTIGFAIYE 460
Cdd:smart00720   1 WHTKSVQGSWTRGQTAGGCRNYPATFWTNPQFRITLEEPDDDD------CTVLIALMQKNRRRLRRKGADFLTIGFAVYK 74

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 826307938   461 VPKEMHgnkqhLQKDFFLYNASKARSKTYINMREVSQRFRLPPSEYVIVPSTYEPHQEGEFILRVFSEKR 530
Cdd:smart00720  75 VPKELH-----LRRDFFLSNAPRASSGDYINGREVSERFRLPPGEYVIVPSTFEPNQEGDFLLRVFSEGP 139

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 826307938 562 FRNIFKQIAGDDMEICADELKNVLNTVVNKHKDLKSQGFTLESCRSMIALMDTDGSGRLNLQEFHHLWKKIKAWQKIFKH 641
Cdd:cd16199    2 FRRLFAQLAGEDAEISAFELQTILRRVLAKREDIKSDGFSIETCKIMVDMLDSDGSGKLGLKEFYILWTKIQKYQKIYRE 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 826307938 642 YDTDQSGTINSYEMRNAVNDAGFHLNSQLYDIITMRYADRHMNIDFDSFICCFIRLEGMFRAFNAFDKDGDGIIKLNVLE 721
Cdd:cd16199   82 IDVDRSGTMNSYEMRKALEEAGFKLPCQLHQVIVARFADDDLIIDFDNFVRCLVRLETLFKIFKQLDPENTGTIELDLIS 161

                 ....*.
gi 826307938 722 WLQLTM 727
Cdd:cd16199  162 WLSFSV 167

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 826307938 561 QFRNIFKQIAGDDMEICADELKNVLNTVVNKhkDLKSQGFTLESCRSMIALMDTDGSGRLNLQEFHHLWKKIKAWQKIFK 640
Cdd:cd16196    1 RLRRLFDKIAGEDMEIDAYELQDILNTAFKK--DFPFDGFSLDACRSMVAMMDVDRSGKLGFEEFKKLWEDLRSWKRVFK 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 826307938 641 HYDTDQSGTINSYEMRNAVNDAGFHLNSQLYDIITMRYADRHMNIDFDSFICCFIRLEGMFRAFNAFDKDGDGIIKLNVL 720
Cdd:cd16196   79 LFDTDGSGSFSSFELRNALNSAGFRLSNATLNALVLRYSNKDGRISFDDFIMCAVKLKTMFEIFKEKDPRGGGRATFNLD 158

                 ....*....
gi 826307938 721 EWLQLTMYA 729
Cdd:cd16196  159 EFLESTMYS 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 826307938 562 FRNIFKQIAGDDMEICADELKNVLNTVVNKHKDLKSQGFTLESCRSMIALMDTDGSGRLNLQEFHHLWKKIKAWQKIFKH 641
Cdd:cd16193    2 SLHLFKIVANEDKEVDMYELQKLLNRMAIKFKSFKTKGFSLDVCRRMINLMDKDGSGKLGLHEFKILWKKIKKWMEIFKE 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 826307938 642 YDTDQSGTINSYEMRNAVNDAGFHLNSQLYDIITMRYADRHMNIDFDSFICCFIRLEGMFRAFNAFDKDGDGIIKLNVLE 721
Cdd:cd16193   82 CDQDRSGNLNSYEMRLAIEKAGIKMNNRVTEVVVARYADDNMIVDFDSFINCFLRLKAMFAFFLSMDTKKTGSICLSINQ 161

                 ....*..
gi 826307938 722 WLQLTMY 728
Cdd:cd16193  162 WLQITMW 168

Penta-EF hand, calcium binding motifs, found in sorcin, grancalcin, and similar proteins; The family corresponds to the second group of penta-EF hand (PEF) proteins that includes sorcin, grancalcin, and similar proteins. Sorcin, also termed 22 kDa Ca2+-binding protein, CP-22, or V19, is a soluble resistance-related calcium-binding protein that is expressed in normal mammalian tissues, such as the liver, lungs and heart. It contains a flexible glycine and proline-rich N-terminal extension and five EF-hand motifs that associate with membranes in a calcium-dependent manner. It may harbor three potential Ca2+ binding sites through its EF1, EF2 and EF3 hands. However, binding of only two Ca2+/monomer suffices to trigger the conformational change that exposes hydrophobic regions and leads to interaction with the respective targets. Sorcin forms homodimers through the association of the unpaired EF5 hand. Among the PEF proteins, sorcin is unique in that it contains potential phosphorylation sites by cAMP-dependent protein kinase (PKA), and it can form a tetramer at slightly acid pH values although remaining a stable dimer at neutral pH. Grancalcin (GCA) is a cytosolic Ca2+-binding protein specifically expressed in neutrophils and monocytes/macrophages. It can strongly interact with sorcin to form a heterodimer and further modulate the function of sorcin. GCA exists as homodimers in solution. It contains five EF-hand motifs attached to an N-terminal region of an approximately 50 residue-long segment rich in glycines and prolines. In contrast with sorcin, GCA binds two Ca2+ ions through its EF1 and EF3 hands.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 826307938 566 FKQIAGDDMEICADELKNVLnTVVNKHKDLksQGFTLESCRSMIALMDTDGSGRLNLQEFHHLWKKIKAWQKIFKHYDTD 645
Cdd:cd16181    6 FSAVAGQDGQIDADELQRCL-TQSGISGNY--QPFSLETCRLMIAMLDRDHSGKMGFNEFKELWAALNQWKTTFMQYDRD 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 826307938 646 QSGTINSYEMRNAVNDAGFHLNSQLYDIITMRYADRHmNIDFDSFICCFIRLEGMFRAFNAFDKDGDGIIKLNVLEWLQL 725
Cdd:cd16181   83 RSGTVEPQELQQAIRSFGYNLSPQALNVIVKRYSKNG-RITFDDFVACAVRLRALTDRFRRRDTQQNGTATFQYDDFIQV 161

                 ..
gi 826307938 726 TM 727
Cdd:cd16181  162 TM 163

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 826307938 566 FKQIAGDDMEICADELKNVLNT--VVNKHKDlksqgFTLESCRSMIALMDTDGSGRLNLQEFHHLWKKIKAWQKIFKHYD 643
Cdd:cd16187    6 FAAVAGQDGQIDADELQRCLTQsgIAGGYKP-----FNLETCRLMISMLDRDMSGTMGFNEFKELWAVLNGWRQHFISFD 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 826307938 644 TDQSGTINSYEMRNAVNDAGFHLNSQLYDIITMRYADrHMNIDFDSFICCFIRLEGMFRAFNAFDKDGDGIIKLNVLEWL 723
Cdd:cd16187   81 SDRSGTVDPQELQKALTTMGFRLSPQAVNSIAKRYST-NGKITFDDYIACCVKLRALTDSFRRRDTSQQGVVNFPYDDFI 159

                 ....
gi 826307938 724 QLTM 727
Cdd:cd16187  160 QCVM 163

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 826307938 566 FKQIAGDDMEICADELKNVLnTVVNKHKDLKSqgFTLESCRSMIALMDTDGSGRLNLQEFHHLWKKIKAWQKIFKHYDTD 645
Cdd:cd16186    6 FSAVAGQDGEVDAEELQRCL-TQSGINGTYTP--FSLETCRIMIAMLDRDHTGKMGFNEFKELWAALNAWKQNFMTVDQD 82