ADP/ATP transporter on adenylate translocase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990602 211 VAGGGAGAVSRTCTAPLDRLKVLMQVHAS----RSNNM----GIIGGFTQMIREGGARSLWRGNGINVLKIAPESAIKFM 282
Cdd:PTZ00169  12 LMGGISAAISKTAVAPIERVKMLIQTQDSipeiKSGKVprysGIVNCFRRVSKEQGVLSLWRGNTANVIRYFPTQAFNFA 91

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990602 283 AYEQIKRLVGS-DQET---LRIHERLVAGSLAGAIAQSSIYPMEVLKTRMA--LRKTG--QYSGMLDCARRILAREGVAA 354
Cdd:PTZ00169  92 FKDYFKNMFPKyNQKTdfwKFFGVNILSGGLAGASSLLIVYPLDFARTRLAsdIGKGGdrEFTGLFDCLMKISKQTGFLS 171

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990602 355 FYKGYVPNMLGIIPYAGIDLAVYETLKNAWLQryavNSADPGVFVLLACGTMSSTCGQLASYPLALVRTRMQAQASIEGA 434
Cdd:PTZ00169 172 LYQGFGVSVQGIIVYRGAYFGLYDSAKALLFG----NDKNTNILYKWAVAQTVTILAGLISYPFDTVRRRMMMMSGRKAK 247

                        250       260       270
                 ....*....|....*....|....*....|....
gi 966990602 435 PEVTMSS---LFKQILRTEGAFGLYRGLAPNFMK 465
Cdd:PTZ00169 248 SEIQYTGtldCWKKILKNEGLGGFFKGAWANVLR 281

ADP/ATP transporter on adenylate translocase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990602 211 VAGGGAGAVSRTCTAPLDRLKVLMQVHAS----RSNNM----GIIGGFTQMIREGGARSLWRGNGINVLKIAPESAIKFM 282
Cdd:PTZ00169  12 LMGGISAAISKTAVAPIERVKMLIQTQDSipeiKSGKVprysGIVNCFRRVSKEQGVLSLWRGNTANVIRYFPTQAFNFA 91

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990602 283 AYEQIKRLVGS-DQET---LRIHERLVAGSLAGAIAQSSIYPMEVLKTRMA--LRKTG--QYSGMLDCARRILAREGVAA 354
Cdd:PTZ00169  92 FKDYFKNMFPKyNQKTdfwKFFGVNILSGGLAGASSLLIVYPLDFARTRLAsdIGKGGdrEFTGLFDCLMKISKQTGFLS 171

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990602 355 FYKGYVPNMLGIIPYAGIDLAVYETLKNAWLQryavNSADPGVFVLLACGTMSSTCGQLASYPLALVRTRMQAQASIEGA 434
Cdd:PTZ00169 172 LYQGFGVSVQGIIVYRGAYFGLYDSAKALLFG----NDKNTNILYKWAVAQTVTILAGLISYPFDTVRRRMMMMSGRKAK 247

                        250       260       270
                 ....*....|....*....|....*....|....
gi 966990602 435 PEVTMSS---LFKQILRTEGAFGLYRGLAPNFMK 465
Cdd:PTZ00169 248 SEIQYTGtldCWKKILKNEGLGGFFKGAWANVLR 281

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990602  68 AEQFPKKIVQAGDKDLDGQLDFEEFVHY-----LQDHEKKLRLVFKSLDKKNDGRIDAQEIMQSLRDLGVkiSEQQAEKI 142
Cdd:COG5126   31 FRRLWATLFSEADTDGDGRISREEFVAGmeslfEATVEPFARAAFDLLDTDGDGKISADEFRRLLTALGV--SEEEADEL 108

                         90       100
                 ....*....|....*....|....*
gi 966990602 143 LKSMDKNGTMTIDWNE----WRDYH 163
Cdd:COG5126  109 FARLDTDGDGKISFEEfvaaVRDYY 133

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 966990602  100 EKKLRLVFKSLDKKNDGRIDAQEIMQSLR--DLGVKISEQQAEKILKSMDKNGTMTIDWNE 158
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRklEEGEPLSDEEVEELFKEFDLDKDGRISFEE 61

ADP/ATP transporter on adenylate translocase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990602 211 VAGGGAGAVSRTCTAPLDRLKVLMQVHAS----RSNNM----GIIGGFTQMIREGGARSLWRGNGINVLKIAPESAIKFM 282
Cdd:PTZ00169  12 LMGGISAAISKTAVAPIERVKMLIQTQDSipeiKSGKVprysGIVNCFRRVSKEQGVLSLWRGNTANVIRYFPTQAFNFA 91

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990602 283 AYEQIKRLVGS-DQET---LRIHERLVAGSLAGAIAQSSIYPMEVLKTRMA--LRKTG--QYSGMLDCARRILAREGVAA 354
Cdd:PTZ00169  92 FKDYFKNMFPKyNQKTdfwKFFGVNILSGGLAGASSLLIVYPLDFARTRLAsdIGKGGdrEFTGLFDCLMKISKQTGFLS 171

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990602 355 FYKGYVPNMLGIIPYAGIDLAVYETLKNAWLQryavNSADPGVFVLLACGTMSSTCGQLASYPLALVRTRMQAQASIEGA 434
Cdd:PTZ00169 172 LYQGFGVSVQGIIVYRGAYFGLYDSAKALLFG----NDKNTNILYKWAVAQTVTILAGLISYPFDTVRRRMMMMSGRKAK 247

                        250       260       270
                 ....*....|....*....|....*....|....
gi 966990602 435 PEVTMSS---LFKQILRTEGAFGLYRGLAPNFMK 465
Cdd:PTZ00169 248 SEIQYTGtldCWKKILKNEGLGGFFKGAWANVLR 281

Mitochondrial carrier protein;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990602  206 WWRHLVAGGGAGAVSRTCTAPLDRLKVLMQVHA--SRSNNMGIIGGFTQMIREGGARSLWRGNGINVLKIAPESAIKFMA 283
Cdd:pfam00153   5 FLASLLAGGIAGAIAVTVTYPLDVVKTRLQVQGgsGKSKGRGILDCFKKIYKEEGIRGLYKGLLPNLLRVAPAAAIYFGT 84

                          90
                  ....*....|.
gi 966990602  284 YEQIKRLVGSD 294
Cdd:pfam00153  85 YETLKRLLLKK 95

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990602  68 AEQFPKKIVQAGDKDLDGQLDFEEFVHY-----LQDHEKKLRLVFKSLDKKNDGRIDAQEIMQSLRDLGVkiSEQQAEKI 142
Cdd:COG5126   31 FRRLWATLFSEADTDGDGRISREEFVAGmeslfEATVEPFARAAFDLLDTDGDGKISADEFRRLLTALGV--SEEEADEL 108

                         90       100
                 ....*....|....*....|....*
gi 966990602 143 LKSMDKNGTMTIDWNE----WRDYH 163
Cdd:COG5126  109 FARLDTDGDGKISFEEfvaaVRDYY 133

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 966990602 102 KLRLVFKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKSMDKNGTMTIDWNEWRD 161
Cdd:cd00051    1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLE 60

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 966990602  100 EKKLRLVFKSLDKKNDGRIDAQEIMQSLR--DLGVKISEQQAEKILKSMDKNGTMTIDWNE 158
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRklEEGEPLSDEEVEELFKEFDLDKDGRISFEE 61

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 966990602  45 LGKQDGRAEATEKRPTILLVVGPAEQFP------KKIVQAGDKDLDGQLDFEEFvHYLQDHEKKLRLVFKSLDKKNDGRI 118
Cdd:cd15897    9 VAGDDGEISATELQQALSNVGWTHFDLGfsletcRSMIAMMDRDHSGKLNFSEF-KGLWNYIKAWQEIFRTYDTDGSGTI 87

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 966990602 119 DAQEIMQSLRDLGVKISEQQAEKILKSMDK-NGTMTID 155
Cdd:cd15897   88 DSNELRQALSGAGYRLSEQTYDIIIRRYDRgRGNIDFD 125

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 966990602 102 KLRLVFKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKSMDKNGTMTIDWNEWRD-YHLLHpveNIPEIILYWK 179
Cdd:cd15898    1 WLRRQWIKADKDGDGKLSLKEIKKLLKRLNIRVSEKELKKLFKEVDTNGDGTLTFDEFEElYKSLT---ERPELEPIFK 76

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 966990602  80 DKDLDGQLDFEEFVHYLQDHEKKLRLV-----FKS-LDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKS--MDKNGT 151
Cdd:cd16227  169 DKDNDGFISFQEFLGDRAGHEDKEWLLvekdrFDEdYDKDGDGKLDGEEILSWLVPDNEEIAEEEVDHLFASadDDHDDR 248

                 ....
gi 966990602 152 MTID 155
Cdd:cd16227  249 LSFD 252

EF-hand, calcium binding motif, found in peflin and similar proteins; Peflin, also termed penta-EF hand (PEF) protein with a long N-terminal hydrophobic domain, or penta-EF hand domain-containing protein 1, is a ubiquitously expressed 30-kD PEF protein containing five EF-hand motifs in its C-terminal domain and a longer N-terminal hydrophobic domain (NHB domain) than any other member of the PEF family. The NHB domain harbors nine repeats of a nonapeptide (A/PPGGPYGGP). Peflin may modulate the function of ALG-2 in Ca2+ signaling. It exists only as a heterodimer with ALG-2, and binds two Ca2+ ions through its EF1 and EF3 hands. Its additional EF5 hand is unpaired and does not bind Ca2+ ion but mediates the heterodimerization with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+. In lower vertebrates, peflin may interact with transient receptor potential N (TRPN1), suggesting a potential role of peflin in fast transducer channel adaptation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990602  80 DKDLDGQLDFEEFV---HYLQdhekKLRLVFKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKSMD--KNGTMTI 154
Cdd:cd16184   47 DKDKSGTIDIYEFQalwNYIQ----QWKQVFQQFDRDRSGSIDENELHQALSQMGYRLSPQFVQFLVSKYDprARRSLTL 122

                 .
gi 966990602 155 D 155
Cdd:cd16184  123 D 123

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 966990602  80 DKDLDGQLDFEEFVHYLQDH-----EKKLRLVFKSLDKKNDGRIDAQEIMQ 125
Cdd:cd00051   10 DKDGDGTISADELKAALKSLgeglsEEEIDEMIREVDKDGDGKIDFEEFLE 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 966990602  73 KKIVQAGDKDLDGQLDFEEFvHYLQDHEKKLRLVFKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKSM-DKNGT 151
Cdd:cd16188   46 RSMVAVMDSDTTGKLGFEEF-KYLWNNIKKWQGIYKQFDTDRSGTIGSQELPGAFEAAGFHLNEQLYQMIIRRYsDEDGN 124

                 ....
gi 966990602 152 MTID 155
Cdd:cd16188  125 MDFD 128

EF-hand domain pair;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 966990602   80 DKDLDGQLDFEEFVHYLQDH-------EKKLRLVFKSLDKKNDGRIDAQEIMQ 125
Cdd:pfam13499  12 DSDGDGYLDVEELKKLLRKLeegeplsDEEVEELFKEFDLDKDGRISFEEFLE 64

EF-hand motif found in phosphoinositide phospholipase C delta (PI-PLC-delta); PI-PLC-delta isozymes represent a class of metazoan PI-PLCs that are some of the most sensitive to calcium among all PLCs. Their activation is modulated by intracellular calcium ion concentration, phospholipids, polyamines, and other proteins, such as RhoAGAP. Like other PI-PLC isozymes, PI-PLC-delta isozymes contain 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 C-terminal C2 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. There are three PI-PLC-delta isozymes (1, 3 and 4). PI-PLC-delta1 is relatively well characterized. It is activated by high calcium levels generated by other PI-PLC family members, and therefore functions as a calcium amplifier within the cell. Different PI-PLC-delta isozymes have different tissue distribution and different subcellular locations. PI-PLC-delta1 is mostly a cytoplasmic protein, PI-PLC-delta3 is located in the membrane, and PI-PLC-delta4 is predominantly detected in the cell nucleus. PI-PLC-delta isozymes is evolutionarily conserved even in non-mammalian species, such as yeast, slime molds and plants.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990602 103 LRLVFKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKSMDKNGTMTIDWNEWRD-YHLLhpvENIPEIilywkhS 181
Cdd:cd16202    2 LKDQFRKADKNGDGKLSFKECKKLLKKLNVKVDKDYAKKLFQEADTSGEDVLDEEEFVQfYNRL---TKRPEI------E 72

                         90       100
                 ....*....|....*....|....*
gi 966990602 182 TIFDV----GENLTVPD--EFTVEE 200
Cdd:cd16202   73 ELFKKysgdDEALTVEElrRFLQEE 97

EF-hand, calcium binding motif, found in homologs of mammalian apoptosis-linked gene 2 protein (ALG-2); The family includes some homologs of mammalian apoptosis-linked gene 2 protein (ALG-2) mainly found in lower eukaryotes, such as a parasitic protist Leishmarua major and a cellular slime mold Dictyostelium discoideum. These homologs contains five EF-hand motifs. Due to the presence of unfavorable residues at the Ca2+-coordinating positions, their non-canonical EF4 and EF5 hands may not bind Ca2+. Two Dictyostelium PEF proteins are the prototypes of this family. They may bind to cytoskeletal proteins and/or signal-transducing proteins localized to detergent-resistant membranes named lipid rafts, and occur as monomers or weak homo- or heterodimers like ALG-2. They can serve as a mediator for Ca2+ signaling-related Dictyostehum programmed cell death (PCD).

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 966990602 103 LRLVFKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKSMDKNGTMTIDWNEwrdYHLLH 166
Cdd:cd16185    2 LRQWFRAVDRDRSGSIDVNELQKALAGGGLLFSLATAEKLIRMFDRDGNGTIDFEE---FAALH 62

EF-hand, calcium binding motif, found in reticulocalbin-2 (RCN2); RCN2, also termed calcium-binding protein ERC-55, or E6-binding protein (E6BP), or TCBP-49, is an endoplasmic reticulum resident low-affinity Ca2+-binding protein that has been implicated in immunity, redox homeostasis, cell cycle regulation and coagulation. It is associated with tumorigenesis, in particular with transformation of cells of the cervix induced by human papillomavirus (HPV), through binding to human papillomavirus (HPV) E6 oncogenic protein. It specifically interacts with vitamin D receptor among nuclear receptors. RCN2 contains an N-terminal signal sequence followed by six copies of the EF-hand Ca2+-binding motif, and 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 966990602  80 DKDLDGQLDFEEFV-HYLQDH----------EKKLRLVfKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKSMDK 148
Cdd:cd16224  171 DKDGDGFISLEEFLgDYRKDPtanedpewiiVEKDRFV-NDYDKDNDGKLDPQELLPWVVPNNYGIAQEEALHLIDEMDL 249

                 ..
gi 966990602 149 NG 150
Cdd:cd16224  250 NG 251

EF-hand, calcium binding motif, found in CREC-EF hand family; The CREC (Cab45/reticulocalbin/ERC45/calumenin)-EF hand family contains a group of six EF-hand, low-affinity Ca2+-binding proteins, including reticulocalbin (RCN-1), ER Ca2+-binding protein of 55 kDa (ERC-55, also known as TCBP-49 or E6BP), reticulocalbin-3 (RCN-3), Ca2+-binding protein of 45 kDa (Cab45 and its splice variant Cab45b), and calumenin ( also known as crocalbin or CBP-50). The proteins are not only localized in various parts of the secretory pathway, but also found in the cytosolic compartment and at the cell surface. They interact with different ligands or proteins and have been implicated in the secretory process, chaperone activity, signal transduction as well as in a large variety of disease processes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990602  73 KKIVQAGDKDLDGQLDFEEFV-------------HYLQDHEKKLRLVFkslDKKNDGRIDAQEIMQSLRDLGVKISEQQA 139
Cdd:cd15899  163 KETLEDLDKNGDGFISLEEFIsdpysadeneeepEWVKVEKERFVELR---DKDKDGKLDGEELLSWVDPSNQEIALEEA 239

                         90       100
                 ....*....|....*....|....
gi 966990602 140 EKILKSMDKNGTMTIDWNEWRDYH 163
Cdd:cd15899  240 KHLIAESDENKDGKLSPEEILDNH 263

EF-hand, calcium binding motif, found in 45 kDa calcium-binding protein (Cab45); Cab45, also termed stromal cell-derived factor 4 (SDF-4), is a soluble, lumenal Golgi resident low-affinity Ca2+-binding protein that contains six copies of the EF-hand Ca2+-binding motif. It is required for secretory pathway calcium ATPase1 (SPCA1)-dependent Ca2+ import into the trans-Golgi network (TGN) and plays an essential role in Ca2+-dependent secretory cargo sorting at the TGN.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990602  88 DFEEfvhyLQDHEKKLRL--VFKSLDKKNDGRIDAQE----IMQSLRDlGVKISEQQAEKILKSMDKNGTMTIDWNEWRD 161
Cdd:cd16225   23 EFEE----DSEPKKRKKLkeIFKKVDVNTDGFLSAEEledwIMEKTQE-HFQEAVEENEQIFKAVDTDKDGNVSWEEYRV 97

                 ....*
gi 966990602 162 YHLLH 166
Cdd:cd16225   98 HFLLS 102

N-terminal domain of Myosin essential light chain ELC; ELC is part of the apicomplexan membrane-associated protein complex called the glideosome, which is essential for parasite motility. The glideosome is composed of six proteins: myosin A (MyoA), essential light chain ELC, myosin light chain MLC1 (also called MTIP), and the glideosome-associated proteins GAP40, GAP45, and GAP50. MyoA is a Class XIV myosin implicated in gliding motility, as well as host cell and tissue invasion by parasites. ELC binds to the MyoA neck region adjacent to the MLC1-binding site, and both myosin light chains co-located to the glideosome. Although ELCs bind to a conserved MyoA sequence, P. falciparum ELC adopts a distinct structure in the free and MyoA-bound state. Therefore ELCs enhance MyoA performance by inducing alpha helical structure formation in MyoA and thus stiffening its lever arm. It has been shown that disruption of MyoA, MLC1, or ELC have dramatic effects on parasite motility but do not affect parasite shape or replication. The ELC N-terminal domain is part of the EF-hand calcium binding motif superfamily. Calcium binding has no effect on the structure of ELCs.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 966990602 100 EKKLRLVFKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKIlksmdkngTMTIDWNEWRDYHLLHPVENIP 172
Cdd:cd22949    2 EEKFREAFILFDRDGDGELTMYEAVLAMRSCGIPLTNDEKDAL--------PASMNWDQFENWAKKKLAYSDP 66

Penta-EF hand, calcium binding motifs, found in PEF calpain family; The PEF calpain family belongs to the second group of penta-EF hand (PEF) proteins. It includes classical (also called conventional or typical) calpain (referring to a calcium-dependent papain-like enzymes, EC 3.4.22.17) large catalytic subunits (CAPN1, 2, 3, 8, 9, 11, 12, 13, 14) and two calpain small subunits (CAPNS1 and CAPNS2), which are largely confined to animals (metazoans). These PEF-containing are nonlysosomal intracellular calcium-activated intracellular cysteine proteases that play important roles in the degradation or functional modulation in a variety of substrates in response to calcium signalling. The classical mu- and m-calpains are heterodimers consisting of homologous but a distinct (large) L-subunit/chain (CAPN1 or CAPN2) and a common (small) S-subunit/chain (CAPNS1 or CAPNS2). These L-subunits (CAPN1 and CAPN2) and S-subunit CAPNS1 are ubiquitously found in all tissues. Other calpains likely consist of an isolated L-subunit/chain alone. Many of them, such as CAPNS2, CAPN3 (in skeletal muscle, or lens), CAPN8 (in stomach), CAPN9 (in digestive tracts), CAPN11 (in testis), CAPN12 (in follicles), are tissue-specific and have specific functions in distinct organs. The L-subunits of similar structure (called CALPA and B) also have been found in Drosophila melanogaster. The S-subunit seems to have a chaperone-like function for proper folding of the L-subunit. The catalytic L-subunits contain a short N-terminal anchor helix, followed by a calpain cysteine protease (CysPc) domain, a C2-domain-like (C2L) domain, and a C-terminal Ca2+-binding penta-EF-hand (PEF) domain. The S-subunits only have the PEF domain following an N-terminal Gly-rich hydrophobic domain. The calpains undergo a rearrangement of the protein backbone upon Ca2+-binding.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990602  73 KKIVQAGDKDLDGQLDFEEFvHYLQDHEKKLRLVFKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKI-LKSMDKNGT 151
Cdd:cd16182   45 RSLIALMDTNGSGRLDLEEF-KTLWSDLKKWQAIFKKFDTDRSGTLSSYELRKALESAGFHLSNKVLQALvLRYADSTGR 123

                 ....
gi 966990602 152 MTID 155
Cdd:cd16182  124 ITFE 127

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.

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                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 966990602  80 DKDLDGQLDFEEFVHYLQDhekkLRL---VFKSLDKKNDGRIDAQEIMQSLRDLGVKIS 135
Cdd:cd16196   51 DVDRSGKLGFEEFKKLWED----LRSwkrVFKLFDTDGSGSFSSFELRNALNSAGFRLS 105

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.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966990602  80 DKDLDGQLDFEEFVHyLQDHEKKLRLVFKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKI-LKSMDKNgtMTIDWNE 158
Cdd:cd16190   53 DTDGSGKLNLQEFRH-LWNKIKQWQKIFKRYDTDKSGTINSYEMRNAVNDAGFRLNNQLYDIItMRYADKH--MNIDFDS 129

                 .
gi 966990602 159 W 159
Cdd:cd16190  130 F 130

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.

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                 ....*....|....*....|....*....|....*
gi 966990602  63 LVVGPAEQFPKKIVQAGDKDLDGQLDFEEFVHYLQ 97
Cdd:cd00051   29 LGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63