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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990596  48 RLWRLFQTLDVNRDGGLCVNDLAVGLRRLglhrtegeLRKIVQAGDKDLDGQLDFEEFVHY-----LQDHEKKLRLVFKS 122
Cdd:COG5126    6 KLDRRFDLLDADGDGVLERDDFEALFRRL--------WATLFSEADTDGDGRISREEFVAGmeslfEATVEPFARAAFDL 77

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990596 123 LDKKNDGRIDAQEIMQSLRDLGVkiSEQQAEKILKRIrtghfwgpvtymDKNGTMTIDWNE----WRDYH 188
Cdd:COG5126   78 LDTDGDGKISADEFRRLLTALGV--SEEEADELFARL------------DTDGDGKISFEEfvaaVRDYY 133

Mitochondrial carrier protein;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990596  321 ETLRIHERLVAGSLAGAIAQSSIYPMEVLKTRMAL---RKTGQYSGMLDCARRILAREGVAAFYKGYVPNMLGIIPYAGI 397
Cdd:pfam00153   1 SELSFLASLLAGGIAGAIAVTVTYPLDVVKTRLQVqggSGKSKGRGILDCFKKIYKEEGIRGLYKGLLPNLLRVAPAAAI 80

                          90
                  ....*....|....*.
gi 966990596  398 DLAVYETLKNaWLQRY 413
Cdd:pfam00153  81 YFGTYETLKR-LLLKK 95

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990596  53 FQTLDVNRDGGLCVNDLAVGLRRLGLHRTEGELRKIVQAGDKDLDGQLDFEEFVHYLQ------DHEKKLRLVFKSLDKK 126
Cdd:PTZ00184  17 FSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLMArkmkdtDSEEEIKEAFKVFDRD 96

                         90       100       110
                 ....*....|....*....|....*....|.
gi 966990596 127 NDGRIDAQEIMQSLRDLGVKISEQQAEKILK 157
Cdd:PTZ00184  97 GNGFISAAELRHVMTNLGEKLTDEEVDEMIR 127

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 966990596   51 RLFQTLDVNRDGGLCVNDLAVGLRRLGLHR--TEGELRKIVQAGDKDLDGQLDFEEFVHYLQ 110
Cdd:pfam13499   6 EAFKLLDSDGDGYLDVEELKKLLRKLEEGEplSDEEVEELFKEFDLDKDGRISFEEFLELYS 67

Mitochondrial carrier protein;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990596  321 ETLRIHERLVAGSLAGAIAQSSIYPMEVLKTRMAL---RKTGQYSGMLDCARRILAREGVAAFYKGYVPNMLGIIPYAGI 397
Cdd:pfam00153   1 SELSFLASLLAGGIAGAIAVTVTYPLDVVKTRLQVqggSGKSKGRGILDCFKKIYKEEGIRGLYKGLLPNLLRVAPAAAI 80

                          90
                  ....*....|....*.
gi 966990596  398 DLAVYETLKNaWLQRY 413
Cdd:pfam00153  81 YFGTYETLKR-LLLKK 95

Mitochondrial carrier protein;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990596  419 DPGVFVLLACGTMSSTCGQLASYPLALVRTRMQAQASIEGAPEVTMSSLFKQILRTEGAFGLYRGLAPNFMKVIPAVSIS 498
Cdd:pfam00153   2 ELSFLASLLAGGIAGAIAVTVTYPLDVVKTRLQVQGGSGKSKGRGILDCFKKIYKEEGIRGLYKGLLPNLLRVAPAAAIY 81

                          90
                  ....*....|..
gi 966990596  499 YVVYENLKITLG 510
Cdd:pfam00153  82 FGTYETLKRLLL 93

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990596  53 FQTLDVNRDGGLCVNDLAVGLRRLGLHRTEGELRKIVQAGDKDLDGQLDFEEFVHYLQ------DHEKKLRLVFKSLDKK 126
Cdd:PTZ00184  17 FSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLMArkmkdtDSEEEIKEAFKVFDRD 96

                         90       100       110
                 ....*....|....*....|....*....|.
gi 966990596 127 NDGRIDAQEIMQSLRDLGVKISEQQAEKILK 157
Cdd:PTZ00184  97 GNGFISAAELRHVMTNLGEKLTDEEVDEMIR 127

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990596  46 RLRLWR-LFQTLDVNRDGGLCVNDLAVGLRRLGLHRTEGELRKIVQAGDKDLDGQLDFEEFVHYLQDH---EKKLRLVFK 121
Cdd:COG5126   31 FRRLWAtLFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDLLDTDGDGKISADEFRRLLTALgvsEEEADELFA 110

                         90       100
                 ....*....|....*....|.
gi 966990596 122 SLDKKNDGRIDAQEIMQSLRD 142
Cdd:COG5126  111 RLDTDGDGKISFEEFVAAVRD 131

ADP/ATP transporter on adenylate translocase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990596 235 LVAGGGAGAVSRTCTAPLD----RLKVLMQVHASRSNNmGIIGGFTQMIREGGARSLWRGNGINVLKIAPESAIKFMAYE 310
Cdd:PTZ00169 117 ILSGGLAGASSLLIVYPLDfartRLASDIGKGGDREFT-GLFDCLMKISKQTGFLSLYQGFGVSVQGIIVYRGAYFGLYD 195

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990596 311 QIKRLV-GSDQETLRIHERLVAGS---LAGAIAqssiYPMEVLKTRMAL---RKTG---QYSGMLDCARRILAREGVAAF 380
Cdd:PTZ00169 196 SAKALLfGNDKNTNILYKWAVAQTvtiLAGLIS----YPFDTVRRRMMMmsgRKAKseiQYTGTLDCWKKILKNEGLGGF 271

                 ....*....
gi 966990596 381 YKGYVPNML 389
Cdd:PTZ00169 272 FKGAWANVL 280

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 966990596   51 RLFQTLDVNRDGGLCVNDLAVGLRRLGLHR--TEGELRKIVQAGDKDLDGQLDFEEFVHYLQ 110
Cdd:pfam13499   6 EAFKLLDSDGDGYLDVEELKKLLRKLEEGEplSDEEVEELFKEFDLDKDGRISFEEFLELYS 67

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 966990596  53 FQTLDVNRDGGLCVNDLAVGLRRLGLHRTEGELRKIVQAGDKDLDGQLDFEEFVHYLQ 110
Cdd:cd00051    6 FRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

EF-hand, calcium binding motif; A diverse superfamily of calcium sensors and calcium signal modulators; most examples in this alignment model have 2 active canonical EF hands. Ca2+ binding induces a conformational change in the EF-hand motif, leading to the activation or inactivation of target proteins. EF-hands tend to occur in pairs or higher copy numbers.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 966990596 115 KLRLVFKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKRirtghfwgpvtyMDKNGTMTIDWNEWRD 186
Cdd:cd00051    1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIRE------------VDKDGDGKIDFEEFLE 60

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 966990596  86 RKIVQAGDKDLDGQLDFEEFvHYLQDHEKKLRLVFKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKRirtghfw 165
Cdd:cd16188   46 RSMVAVMDSDTTGKLGFEEF-KYLWNNIKKWQGIYKQFDTDRSGTIGSQELPGAFEAAGFHLNEQLYQMIIRR------- 117

                         90
                 ....*....|....*
gi 966990596 166 gpvtYMDKNGTMTID 180
Cdd:cd16188  118 ----YSDEDGNMDFD 128

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

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 966990596  42 DPDHRLRLWRLFQTLDVNRDGGLCVNDLAVGLRRLGLhrTEGELRKIVQAGDKDLDGQLDFEEFVHYLQDH 112
Cdd:COG5126   64 EATVEPFARAAFDLLDTDGDGKISADEFRRLLTALGV--SEEEADELFARLDTDGDGKISFEEFVAAVRDY 132

EF-hand, calcium binding motif; A diverse superfamily of calcium sensors and calcium signal modulators; most examples in this alignment model have 2 active canonical EF hands. Ca2+ binding induces a conformational change in the EF-hand motif, leading to the activation or inactivation of target proteins. EF-hands tend to occur in pairs or higher copy numbers.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990596  84 ELRKIVQAGDKDLDGQLDFEEFVHYLQDH-----EKKLRLVFKSLDKKNDGRIDAQEIMQ 138
Cdd:cd00051    1 ELREAFRLFDKDGDGTISADELKAALKSLgeglsEEEIDEMIREVDKDGDGKIDFEEFLE 60

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 966990596  49 LWRLFQTLDVNRDGGLCVNDLAVGLRRLGLHRTEGE-LRKIVQAGDKDLDGQLDFEEFV---HYLQDHEKklrlVFKSLD 124
Cdd:cd16183    2 LWNVFQRVDKDRSGQISATELQQALSNGTWTPFNPEtVRLMIGMFDRDNSGTINFQEFAalwKYITDWQN----CFRSFD 77

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 966990596 125 KKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKRI-RTGH 163
Cdd:cd16183   78 RDNSGNIDKNELKQALTSFGYRLSDQFYDILVRKFdRQGR 117

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 966990596  93 DKDLDGQLDFEEFV---HYLQdhekKLRLVFKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKR 158
Cdd:cd16184   47 DKDKSGTIDIYEFQalwNYIQ----QWKQVFQQFDRDRSGSIDENELHQALSQMGYRLSPQFVQFLVSK 111

EF-hand, calcium binding motif, found in reticulocalbin-2 (RCN2) mainly from protostomes; This family corresponds to a group of uncharacterized RCN2-like proteins, which are mainly found in protostomes. Although their biological function remains unclear, they show high sequence similarity with RCN2 (also known as E6BP or TCBP-49), which is an endoplasmic reticulum resident low-affinity Ca2+-binding protein that has been implicated in immunity, redox homeostasis, cell cycle regulation and coagulation. Members in this family contain six copies of the EF-hand Ca2+-binding motif, but may lack a C-terminal His-Asp-Glu-Leu (HDEL) tetrapeptide that is required for retention of RCN2 in the endoplasmic reticulum (ER).

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990596  52 LFQTLDVNRDGGLCVNDLavglrRLGLHRTEG------ELRKIVQAGDKDLDGQLDFEEFVHYLQDHEKKLRLV-----F 120
Cdd:cd16227  127 MFEAADLNKDGKLDKTEF-----SAFQHPEEYphmhpvLIEQTLRDKDKDNDGFISFQEFLGDRAGHEDKEWLLvekdrF 201

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 966990596 121 KS-LDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKRirtghfwgpvTYMDKNGTMTID 180
Cdd:cd16227  202 DEdYDKDGDGKLDGEEILSWLVPDNEEIAEEEVDHLFAS----------ADDDHDDRLSFD 252

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 966990596  47 LRLWR-LFQTLDVNRDGGLCVNDLAVGLRRLGLHRTEgELRKIVQAGDKDLDGQLDFEEFVHYLQDHEKKLRlVFKSLDK 125
Cdd:cd16188   72 IKKWQgIYKQFDTDRSGTIGSQELPGAFEAAGFHLNE-QLYQMIIRRYSDEDGNMDFDNFISCLVRLDAMFR-AFKSLDK 149

                 ....*.
gi 966990596 126 KNDGRI 131
Cdd:cd16188  150 DGTGQI 155

EF-hand motif found in eukaryotic phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11) isozymes; PI-PLC isozymes are signaling enzymes that hydrolyze the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which goes on to phosphorylate other molecules, leading to altered cellular activity. Calcium is required for the catalysis. This family corresponds to the four EF-hand motifs containing PI-PLC isozymes, including PI-PLC-beta (1-4), -gamma (1-2), -delta (1,3,4), -epsilon (1), -zeta (1), eta (1-2). Lower eukaryotes such as yeast and slime molds contain only delta-type isozymes. In contrast, other types of isoforms present in higher eukaryotes. This family also includes 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase 1 (PLC1) from fungi. Some homologs from plants contain only two atypical EF-hand motifs and they are not included. All PI-PLC isozymes except sperm-specific PI-PLC-zeta share a core set of domains, including an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core, and a single C2 domain. PI-PLC-zeta lacks the PH domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. Most of EF-hand motifs found in PI-PLCs consist of a helix-loop-helix structure, but lack residues critical to metal binding. Moreover, the EF-hand region of most of PI-PLCs may have an important regulatory function, but it has yet to be identified. However, PI-PLC-zeta is a key exception. It is responsible for Ca2+ oscillations in fertilized oocytes and exhibits a high sensitivity to Ca2+ mediated through its EF-hand domain. In addition, PI-PLC-eta2 shows a canonical EF-loop directing Ca2+-sensitivity and thus can amplify transient Ca2+ signals. Also it appears that PI-PLC-delta1 can regulate the binding of PH domain to PIP2 in a Ca2+-dependent manner through its functionally important EF-hand domains. PI-PLCs can be activated by a variety of extracellular ligands, such as growth factors, hormones, cytokines and lipids. Their activation has been implicated in tumorigenesis and/or metastasis linked to migration, proliferation, growth, inflammation, angiogenesis and actin cytoskeleton reorganization. PI-PLC-beta isozymes are activated by G-protein coupled receptor (GPCR) through different mechanisms. However, PI-PLC-gamma isozymes are activated by receptor tyrosine kinase (RTK), such as Rho and Ras GTPases. In contrast, PI-PLC-epsilon are activated by both GPCR and RTK. PI-PLC-delta1 and PLC-eta 1 are activated by GPCR-mediated calcium mobilization. The activation mechanism for PI-PLC-zeta remains unclear.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990596 115 KLRLVFKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKrirtghfwgpvtYMDKNGTMTIDWNEWRD-YHLLHpv 193
Cdd:cd15898    1 WLRRQWIKADKDGDGKLSLKEIKKLLKRLNIRVSEKELKKLFK------------EVDTNGDGTLTFDEFEElYKSLT-- 66

                         90
                 ....*....|.
gi 966990596 194 eNIPEIILYWK 204
Cdd:cd15898   67 -ERPELEPIFK 76

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 966990596  86 RKIVQAGDKDLDGQLDFEEFvhylqdheKKLRLV-------FKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKR 158
Cdd:cd16187   43 RLMISMLDRDMSGTMGFNEF--------KELWAVlngwrqhFISFDSDRSGTVDPQELQKALTTMGFRLSPQAVNSIAKR 114

                         90
                 ....*....|....
gi 966990596 159 IRTGhfwGPVTYMD 172
Cdd:cd16187  115 YSTN---GKITFDD 125

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 966990596  93 DKDLDGQLDFEEFvhylqdheKKL-------RLVFKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKRIRTGHF 164
Cdd:cd16181   50 DRDHSGKMGFNEF--------KELwaalnqwKTTFMQYDRDRSGTVEPQELQQAIRSFGYNLSPQALNVIVKRYSKNGR 120

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 966990596  47 LRLW-RLFQTLDVNRDGGLCVNDLAVGLRRLGLHRTEGELRKIV-QAGDKdlDGQLDFEEFVHYLQdhekKLRL---VFK 121
Cdd:cd16196   70 LRSWkRVFKLFDTDGSGSFSSFELRNALNSAGFRLSNATLNALVlRYSNK--DGRISFDDFIMCAV----KLKTmfeIFK 143

                         90
                 ....*....|
gi 966990596 122 SLDKKNDGRI 131
Cdd:cd16196  144 EKDPRGGGRA 153

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 966990596  52 LFQTLdVNRDGGLCVNDLAVGLRRLGLH----RTEG----ELRKIVQAGDKDLDGQLDFEEFvHYLQDHEKKLRLVFKSL 123
Cdd:cd16193    5 LFKIV-ANEDKEVDMYELQKLLNRMAIKfksfKTKGfsldVCRRMINLMDKDGSGKLGLHEF-KILWKKIKKWMEIFKEC 82

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 966990596 124 DKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKRirtghfwgpvtYMDKNgtMTIDWNEW 184
Cdd:cd16193   83 DQDRSGNLNSYEMRLAIEKAGIKMNNRVTEVVVAR-----------YADDN--MIVDFDSF 130

EF-hand, calcium binding motif, found in parvalbumin-like EF-hand family; The family includes alpha- and beta-parvalbumins, and a group of uncharacterized calglandulin-like proteins. Parvalbumins are small, acidic, cytosolic EF-hand-containing Ca2+-buffer and Ca2+ transporter/shuttle proteins belonging to EF-hand superfamily. They are expressed by vertebrates in fast-twitch muscle cells, specific neurons of the central and peripheral nervous system, sensory cells of the mammalian auditory organ (Corti's cell), and some other cells, and characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. Thus, they may play an additional role in Mg2+ handling. Moreover, parvalbumins represent one of the major animal allergens. In metal-bound states, parvalbumins possess a rigid and stable tertiary structure and display strong allergenicity. In contrast, the metal-free parvalbumins are intrinsically disordered, and the loss of metal ions results in a conformational change that decreases their IgE binding capacity. Furthermore, parvalbumins have been widely used as a neuronal marker for a variety of functional brain systems. They also function as a Ca2+ shuttle transporting Ca2+ from troponin-C (TnC) to the sarcoplasmic reticulum (SR) Ca2+ pump during muscle relaxation. Thus they may facilitate myocardial relaxation and play important roles in cardiac diastolic dysfunction. Parvalbumins consists of alpha- and beta- sublineages, which can be distinguished on the basis of isoelectric point (pI > 5 for alpha; pI

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 966990596  51 RLFQTLDVNRDGGLCVNDLAVGLRRLGLHR---TEGELRKIVQAGDKDLDGQLDFEEF 105
Cdd:cd16251   38 KVFQILDKDKSGFIEEEELKYILKGFSIAGrdlTDEETKALLAAGDTDGDGKIGVEEF 95

EF-hand domain pair;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 966990596   61 DGGLCVNDLAVGLRRLGLHR-TEGELRKIVQAGDKDLDGQLDFEEFVHYLQD 111
Cdd:pfam13833   2 KGVITREELKRALALLGLKDlSEDEVDILFREFDTDGDGYISFDEFCVLLER 53

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 966990596  86 RKIVQAGDKDLDGQLDFEEFVHYLQDhekkLRL---VFKSLDKKNDGRIDAQEIMQSLRDLGVKIS 148
Cdd:cd16196   44 RSMVAMMDVDRSGKLGFEEFKKLWED----LRSwkrVFKLFDTDGSGSFSSFELRNALNSAGFRLS 105