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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 51591899  18 EEIRRLGKSFRKLDLDKSGSLSIEEFMRLPELQQNPLVGRvidiFDTDGNGEVDFHEFIVGTSQfSVKGDEEQKLRFAFR 97
Cdd:COG5126   2 LQRRKLDRRFDLLDADGDGVLERDDFEALFRRLWATLFSE----ADTDGDGRISREEFVAGMES-LFEATVEPFARAAFD 76

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 51591899  98 IYDMDNDGFISNGELFQVLKMMvgnNLKDWQLQQLVDKsilvLDKDGDGRISFEEFSDVVK 158
Cdd:COG5126  77 LLDTDGDGKISADEFRRLLTAL---GVSEEEADELFAR----LDTDGDGKISFEEFVAAVR 130

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 51591899  18 EEIRRLGKSFRKLDLDKSGSLSIEEFMRLPELQQNPLVGRvidiFDTDGNGEVDFHEFIVGTSQfSVKGDEEQKLRFAFR 97
Cdd:COG5126   2 LQRRKLDRRFDLLDADGDGVLERDDFEALFRRLWATLFSE----ADTDGDGRISREEFVAGMES-LFEATVEPFARAAFD 76

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 51591899  98 IYDMDNDGFISNGELFQVLKMMvgnNLKDWQLQQLVDKsilvLDKDGDGRISFEEFSDVVK 158
Cdd:COG5126  77 LLDTDGDGKISADEFRRLLTAL---GVSEEEADELFAR----LDTDGDGKISFEEFVAAVR 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.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 51591899  91 KLRFAFRIYDMDNDGFISNGELFQVLKMMVGNnlkdwQLQQLVDKSILVLDKDGDGRISFEEFSDVVK 158
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKSLGEG-----LSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 51591899   27 FRKLDLDKSGSLSIEEFMRLpeLQQNPLVGRVIDI------FDTDGNGEVDFHEFIVGT------SQFSVKGDEEQKLRF 94
Cdd:NF041410  33 FAKLDSDGDGSVSQDELSSA--LSSKSDDGSLIDLselfsdLDSDGDGSLSSDELAAAAppppppPDQAPSTELADDLLS 110

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 51591899   95 AFriyDMDNDGFISNGELfQVLKMMVGNNLkdwqlqqlvDKSIL--VLDKDGDGRISFEEFS 154
Cdd:NF041410 111 AL---DTDGDGSISSDEL-SAGLTSAGSSA---------DSSQLfsALDSDGDGSVSSDELA 159

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 51591899  18 EEIRRLGKSFRKLDLDKSGSLSIEEFMRLPELQQNPLVGRvidiFDTDGNGEVDFHEFIVGTSQfSVKGDEEQKLRFAFR 97
Cdd:COG5126   2 LQRRKLDRRFDLLDADGDGVLERDDFEALFRRLWATLFSE----ADTDGDGRISREEFVAGMES-LFEATVEPFARAAFD 76

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 51591899  98 IYDMDNDGFISNGELFQVLKMMvgnNLKDWQLQQLVDKsilvLDKDGDGRISFEEFSDVVK 158
Cdd:COG5126  77 LLDTDGDGKISADEFRRLLTAL---GVSEEEADELFAR----LDTDGDGKISFEEFVAAVR 130

centrin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 51591899    1 MGNEASYQTELcnhfDQEEIRRLGKSFRKLDLDKSGSLSIEEF---MRLPELQ-QNPLVGRVIDIFDTDGNGEVDFHEFI 76
Cdd:PTZ00183   1 MRKRRSERPGL----TEDQKKEIREAFDLFDTDGSGTIDPKELkvaMRSLGFEpKKEEIKQMIADVDKDGSGKIDFEEFL 76

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 51591899   77 -VGTSQFSVKGDEEQKLRfAFRIYDMDNDGFISNGELFQVLKMMvGNNLKDWQLQQLVDKSilvlDKDGDGRISFEEFSD 155
Cdd:PTZ00183  77 dIMTKKLGERDPREEILK-AFRLFDDDKTGKISLKNLKRVAKEL-GETITDEELQEMIDEA----DRNGDGEISEEEFYR 150

                 ...
gi 51591899  156 VVK 158
Cdd:PTZ00183 151 IMK 153

Penta-EF hand, calcium binding motifs, found in Group I PEF proteins; The family corresponds to Group I PEF proteins that have been found not only in higher animals but also in lower animals, plants, fungi and protists. Group I PEF proteins include apoptosis-linked gene 2 protein (ALG-2), peflin and similar proteins. ALG-2, also termed programmed cell death protein 6 (PDCD6), is a widely expressed calcium-binding modulator protein associated with cell proliferation and death, as well as cell survival. It forms a homodimer in the cell or a heterodimer with its closest paralog peflin. Among the PEF proteins, ALG-2 can bind three Ca2+ ions through its EF1, EF3, and EF5 hands, where it is unique in that its EF5 hand binds Ca2+ ion in a canonical coordination. Peflin is a ubiquitously expressed 30-kD PEF protein containing five EF-hand motifs in its C-terminal domain and a longer N-terminal hydrophobic domain (NHB domain) than any other member of the PEF family. The NHB domain harbors nine repeats of a nonapeptide (A/PPGGPYGGP). Peflin may modulate the function of ALG-2 in Ca2+ signaling. It exists only as a heterodimer with ALG-2, and binds two Ca2+ ions through its EF1 and EF3 hands. Its additional EF5 hand is unpaired and does not bind Ca2+ ion but mediates the heterodimerization with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 51591899  27 FRKLDLDKSGSLSIEEfmrlpeLQQNPLVGRV-----------IDIFDTDGNGEVDFHEFivgtsqfsvKG--DEEQKLR 93
Cdd:cd16180   6 FQAVDRDRSGRISAKE------LQRALSNGDWtpfsietvrlmINMFDRDRSGTINFDEF---------VGlwKYIQDWR 70

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 51591899  94 FAFRIYDMDNDGFISNGELFQVLKMMvGNNLKDWQLQQLVDKsilvLDKDGDGRISFEEF 153
Cdd:cd16180  71 RLFRRFDRDRSGSIDFNELQNALSSF-GYRLSPQFVQLLVRK----FDRRRRGSISFDDF 125

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        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 51591899  27 FRKLDLDKSGSLSIeefmrlPELQQ-----NPLVG-----RVIDIFDTDGNGEVDFHEFiVGTSQFSvkgdeeQKLRFAF 96
Cdd:cd16185   6 FRAVDRDRSGSIDV------NELQKalaggGLLFSlataeKLIRMFDRDGNGTIDFEEF-AALHQFL------SNMQNGF 72

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 51591899  97 RIYDMDNDGFISNGELFQVLKmMVGNNLKDWQLQQLVDKsilvLDKDGDGRISFEEF 153
Cdd:cd16185  73 EQRDTSRSGRLDANEVHEALA-ASGFQLDPPAFQALFRK----FDPDRGGSLGFDDY 124

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 51591899  27 FRKLDLDKSGSLSIEEfmrlpeLQQ----------NPLVGR-VIDIFDTDGNGEVDFHEFivgTSQFSVKGDEEQklrfA 95
Cdd:cd16183   6 FQRVDKDRSGQISATE------LQQalsngtwtpfNPETVRlMIGMFDRDNSGTINFQEF---AALWKYITDWQN----C 72

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 51591899  96 FRIYDMDNDGFISNGELFQVLKMMvGNNLKDWQLQQLVDKsilvLDKDGDGRISFEEF 153
Cdd:cd16183  73 FRSFDRDNSGNIDKNELKQALTSF-GYRLSDQFYDILVRK----FDRQGRGTIAFDDF 125

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 51591899  25 KSFRKLDLDKSGSLSIEEFMRLP----ELQQNPLVGRVIDIFDTDGNGEVDFHEFI 76
Cdd:cd00051   4 EAFRLFDKDGDGTISADELKAALkslgEGLSEEEIDEMIREVDKDGDGKIDFEEFL 59

EF-hand, calcium binding motif, found in calumenin, reticulocalbin-1 (RCN-1), reticulocalbin-3 (RCN-3), and similar proteins; The family corresponds to a group of six EF-hand Ca2+-binding proteins, including calumenin (also known as crocalbin or CBP-50), reticulocalbin-1 (RCN-1), reticulocalbin-3 (RCN-3), and similar proteins. Calumenin is an endo/sarcoplasmic reticulum (ER/SR) resident low-affinity Ca2+-binding protein that contains six EF-hand domains and a C-terminal SR retention signal His-Asp-Glu-Phe (HDEF) tetrapeptide. It functions as a novel regulator of SERCA2, and its expressional changes are tightly coupled with Ca2+-cycling of cardiomyocytes. It is also broadly involved in haemostasis and in the pathophysiology of thrombosis. Moreover, the extracellular calumenin acts as a suppressor of cell migration and tumor metastasis. RCN-1 is an endoplasmic reticulum resident Ca2+-binding protein with a carboxyl-terminal His-Asp-Glu-Leu (HDEL) tetrapeptide signal. It acts as a potential negative regulator of B-RAF activation and can negatively modulate cardiomyocyte hypertrophy by inhibition of the mitogen-activated protein kinase signalling cascade. It also plays a key role in the development of doxorubicin-associated resistance. RCN-3 is a putative six EF-hand Ca2+-binding protein that contains five RXXR (X is any amino acid) motifs and a C-terminal ER retrieval signal HDEL tetrapeptide. The RXXR motif represents the target sequence of subtilisin-like proprotein convertases (SPCs). RCN-3 is specifically bound to the paired basic amino-acid-cleaving enzyme-4 (PACE4) precursor protein and plays an important role in the biosynthesis of PACE4.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 51591899  14 HFDQ----EEIRRLGKSFRKLDLDKSGSLSIEEFMRLPELQQNPL----VGRVIDIFDTDGNGEVDFHEFIVGTSQFSVK 85
Cdd:cd16226  24 EFDQltpeESKERLGIIVDKIDKNGDGFVTEEELKDWIKYVQKKYiredVDRQWKEYDPNKDGKLSWEEYKKATYGFLDD 103

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 51591899  86 GDEEQKLRFA-----------FRIYDMDNDGFISNGELFQVLKMMVGNNLKDWqlqqLVDKSILVLDKDGDGRISFEEF 153
Cdd:cd16226 104 EEEDDDLHESykkmirrderrWKAADQDGDGKLTKEEFTAFLHPEEFPHMRDI----VVQETLEDIDKNKDGFISLEEY 178

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 51591899  17 QEEIRRLGKSFRKLDLDKSGSLSIEEFMRLPELQQNP-----LVGRVIDIFDTDGNGEVDFHEFIvGTSQFSVKGDEEQK 91
Cdd:cd15899 119 KKLLLKDKKRFEAADQDGDLILTLEEFLAFLHPEESPymldfVIKETLEDLDKNGDGFISLEEFI-SDPYSADENEEEPE 197

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 51591899  92 L----RFAFR-IYDMDNDGFISNGELfqvLKMMVGNNlkDWQLQQLVDKSILVLDKDGDGRISFEE 152
Cdd:cd15899 198 WvkveKERFVeLRDKDKDGKLDGEEL---LSWVDPSN--QEIALEEAKHLIAESDENKDGKLSPEE 258

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        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 51591899  85 KGDEEQKLRFAFRIYDMDNDGFISNGELFQVLKMM--VGNNLKDWQLQQLVDKSilvlDKDGDGRISFEEFSDVVK 158
Cdd:cd16251  29 KQKSEDQIKKVFQILDKDKSGFIEEEELKYILKGFsiAGRDLTDEETKALLAAG----DTDGDGKIGVEEFATLVA 100

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 51591899   27 FRKLDLDKSGSLSIEEFMRLpeLQQNPLVGRVIDI------FDTDGNGEVDFHEFIVGT------SQFSVKGDEEQKLRF 94
Cdd:NF041410  33 FAKLDSDGDGSVSQDELSSA--LSSKSDDGSLIDLselfsdLDSDGDGSLSSDELAAAAppppppPDQAPSTELADDLLS 110

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 51591899   95 AFriyDMDNDGFISNGELfQVLKMMVGNNLkdwqlqqlvDKSIL--VLDKDGDGRISFEEFS 154
Cdd:NF041410 111 AL---DTDGDGSISSDEL-SAGLTSAGSSA---------DSSQLfsALDSDGDGSVSSDELA 159

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 51591899   4 EASYQTELCNHFDQ----EEIRRLGKSFRKLDLDKSGSLSIEEF----MRLPELQQNPLVGRVIDIFDTDGNGEVDFHEF 75
Cdd:cd15899  14 EAFLGKEEAEEFDQltpeESKRRLGVIVSKMDVDKDGFISAKELhswiLESFKRHAMEESKEQFRAVDPDEDGHVSWDEY 93

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 51591899  76 IVGTsqFSVKGDEEQ-----------------KLRFAFRIYDMDNDGFISNGELFQVLKMMVGNNLKDWQLQQLVDKsil 138
Cdd:cd15899  94 KNDT--YGSVGDDEEnvadnikedeeykklllKDKKRFEAADQDGDLILTLEEFLAFLHPEESPYMLDFVIKETLED--- 168

                       170       180
                ....*....|....*....|....
gi 51591899 139 vLDKDGDGRISFEEF-SDVVKTME 161
Cdd:cd15899 169 -LDKNGDGFISLEEFiSDPYSADE 191

EF-hand, calcium binding motif, found in alpha-parvalbumin; Alpha-parvalbumin is cytosolic Ca2+/Mg2+-binding protein expressed mainly in fast-twitch skeletal myofibrils, where it may act as a soluble relaxing factor facilitating the Ca2+-mediated relaxation phase. It is also expressed in rapidly firing neurons, particularly GABA-ergic neurons, and thus may confer protection against Ca2+ toxicity. The major role of alpha-parvalbumin is metal buffering and transport of Ca2+. It binds different metal cations, and exhibits very high affinity for Ca2+ and physiologically significant affinity for Mg2+. Alpha-parvalbumin is 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+. Both metal ion-binding sites in alpha-parvalbumin are high-affinity sites. Additionally, in contrast to beta-parvalbumin, alpha-parvalbumin is less acidic and has an additional residue in the C-terminal helix.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 51591899  84 VKGDEEQKLRFAFRIYDMDNDGFISNGELFQVLKMMV--GNNLKDWQLQQLVDKSilvlDKDGDGRISFEEFSDVV 157
Cdd:cd16254  28 LKKKSADDVKKVFHILDKDKSGFIEEDELKFVLKGFSpdGRDLSDKETKALLAAG----DKDGDGKIGIDEFATLV 99

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 51591899  92 LRFAFRIYDMDNDGFISNGELFQVLKMmvGNNLKDwqlQQLVDKSILVLDKDGDGRISFEEFSDV 156
Cdd:cd16185   2 LRQWFRAVDRDRSGSIDVNELQKALAG--GGLLFS---LATAEKLIRMFDRDGNGTIDFEEFAAL 61

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 51591899  16 DQEEIRRLGKSFRKLDLDKSGSLSIEEFMRLPELQQNP-----LVGRVIDIFDTDGNGEVDFHEFIVGTSQFSV------ 84
Cdd:cd16225 126 DKEVLDRYKDRWSQADEPEDGLLDVEEFLSFRHPEHSRgmlknMVKEILHDLDQDGDEKLTLDEFVSLPPGTVEeqqaed 205

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 51591899  85 KGDEEQKLRFAFRI-YDMDNDGFISNGELFQVLKMMVGNNLKDwQLQQLvdksILVLDKDGDGRISFEE 152
Cdd:cd16225 206 DDEWKKERKKEFEEvIDLNHDGKVTKEELEEYMDPRNERHALN-EAKQL----IAVADENKDGKLSLEE 269

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 51591899  14 HFdQEEIRRLGKSFRKLDLDKSGSLSIEEFMrlpelqqnplvgrvIDIFDTDGNGEVDFHEFIVGTSQFSVKGDEEQKL- 92
Cdd:cd16225  67 HF-QEAVEENEQIFKAVDTDKDGNVSWEEYR--------------VHFLLSKGYSEEEAEEKIKNNEELKLDEDDKEVLd 131

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 51591899  93 --RFAFRIYDMDNDGFISNGELF---------QVLKMMVGNNLKDwqlqqlvdksilvLDKDGDGRISFEEFS 154
Cdd:cd16225 132 ryKDRWSQADEPEDGLLDVEEFLsfrhpehsrGMLKNMVKEILHD-------------LDQDGDEKLTLDEFV 191

serine/threonine protein phosphatase 2A regulatory subunit B" subunit gamma; Heterotrimeric serine/threonine protein phosphatase 2A (PP2A) consists of scaffolding (A), catalytic (C), and variable (B, B', and B") subunits. The variable subunits dictate subcellular localization and substrate specificity of the PP2A holoenzyme. This subfamily includes protein phosphatase subunit G5PR (also known as serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma, G4-1, G5pr, GDRM, SPGF36, or C14orf10) that is encoded by the PPP2R3C gene. It is involved in the control of the dynamic organization of the cortical cytoskeleton and plays an important role in the organization of interphase microtubule arrays in part through the regulation of nucleation geometry. G5PR is involved in the ontogeny of multiple organs, especially critical for testis development and spermatogenesis. PPP2R3C gene variants cause syndromic 46,XY gonadal dysgenesis and impaired spermatogenesis in humans, and thus is emerging as a potential therapeutic target for male infertility.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 51591899  13 NHFDQEEIRRLGKSFRKLDLDKSGSLSIEEFMRLPElqqNPLVGRVID-IFDTDG--NGEVDF---------HEFIvgts 80
Cdd:cd21505 213 NWFSAPSALRVYGQYLNLDKDHNGMLSKQELSRYGK---GTLTSVFIDrVFQECLtyNGEMDYktfldfvlaMENR---- 285

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 51591899  81 qfsvkgDEEQKLRFAFRIYDMDNDGFISNGEL---FQ-VLKMMVGNNLKDWQLQQLVD 134
Cdd:cd21505 286 ------KEPQALQYFFRILDLKGQGYLTPFTLnyfFRaIQEKMKEHGQEPVSFEDVKD 337

Eps15 homology domain; found in proteins implicated in endocytosis, vesicle transport, and signal transduction. The alignment contains a pair of EF-hand motifs, typically one of them is canonical and binds to Ca2+, while the other may not bind to Ca2+. A hydrophobic binding pocket is formed by residues from both EF-hand motifs. The EH domain binds to proteins containing NPF (class I), [WF]W or SWG (class II), or H[TS]F (class III) sequence motifs.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 51591899  25 KSFRKLDLDKSGSLSIEE----FMR--LPelqqNPLVGRVIDIFDTDGNGEVDFHEFIVG 78
Cdd:cd00052   3 QIFRSLDPDGDGLISGDEarpfLGKsgLP----RSVLAQIWDLADTDKDGKLDKEEFAIA 58

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 51591899  27 FRKLDLDkSGSLSIEEFMRL--------PELQQNPLVGR-VIDIFDTDGNGEVDFHEFivgtsqfsvKGDEEQKLRF--A 95
Cdd:cd15897   6 FQAVAGD-DGEISATELQQAlsnvgwthFDLGFSLETCRsMIAMMDRDHSGKLNFSEF---------KGLWNYIKAWqeI 75

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 51591899  96 FRIYDMDNDGFISNGELFQVLKMMvGNNLKDWQLQQLVDKSilvldKDGDGRISFEEF 153
Cdd:cd15897  76 FRTYDTDGSGTIDSNELRQALSGA-GYRLSEQTYDIIIRRY-----DRGRGNIDFDDF 127

Eps15 homology domain; found in proteins implicated in endocytosis, vesicle transport, and signal transduction. The alignment contains a pair of EF-hand motifs, typically one of them is canonical and binds to Ca2+, while the other may not bind to Ca2+. A hydrophobic binding pocket is formed by residues from both EF-hand motifs. The EH domain binds to proteins containing NPF (class I), [WF]W or SWG (class II), or H[TS]F (class III) sequence motifs.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 51591899  96 FRIYDMDNDGFISNGELFQVLKMmvgNNLKDWQLQQLVDKSilvlDKDGDGRISFEEFS 154
Cdd:cd00052   5 FRSLDPDGDGLISGDEARPFLGK---SGLPRSVLAQIWDLA----DTDKDGKLDKEEFA 56

EF-hand, calcium binding motif; EF-hands are calcium-binding motifs that occur at least in pairs. Links between disease states and genes encoding EF-hands, particularly the S100 subclass, are emerging. Each motif consists of a 12 residue loop flanked on either side by a 12 residue alpha-helix. EF-hands undergo a conformational change unpon binding calcium ions.

                           10        20
                   ....*....|....*....|....*....
gi 51591899     91 KLRFAFRIYDMDNDGFISNGELFQVLKMM 119
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

EF hand; The EF-hands can be divided into two classes: signalling proteins and buffering/transport proteins. The first group is the largest and includes the most well-known members of the family such as calmodulin, troponin C and S100B. These proteins typically undergo a calcium-dependent conformational change which opens a target binding site. The latter group is represented by calbindin D9k and do not undergo calcium dependent conformational changes.

                          10        20
                  ....*....|....*....|....*....
gi 51591899    91 KLRFAFRIYDMDNDGFISNGELFQVLKMM 119
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELLKKL 29