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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386763839  20 IRRLGKRFRKLDLDNSGALSIDEFMSLPElqqnPLVQRVIDIFDADGNGEVDFKEFIQGVSQFSVRGDKlSKLRFAFRIY 99
Cdd:COG5126    4 RRKLDRRFDLLDADGDGVLERDDFEALFR----RLWATLFSEADTDGDGRISREEFVAGMESLFEATVE-PFARAAFDLL 78

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 386763839 100 DMDNDGYISNGELFQVLKMMvgnNLKDTQLQQIVDKticfADKDEDGKISFDEFCSVV 157
Cdd:COG5126   79 DTDGDGKISADEFRRLLTAL---GVSEEEADELFAR----LDTDGDGKISFEEFVAAV 129

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386763839  20 IRRLGKRFRKLDLDNSGALSIDEFMSLPElqqnPLVQRVIDIFDADGNGEVDFKEFIQGVSQFSVRGDKlSKLRFAFRIY 99
Cdd:COG5126    4 RRKLDRRFDLLDADGDGVLERDDFEALFR----RLWATLFSEADTDGDGRISREEFVAGMESLFEATVE-PFARAAFDLL 78

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 386763839 100 DMDNDGYISNGELFQVLKMMvgnNLKDTQLQQIVDKticfADKDEDGKISFDEFCSVV 157
Cdd:COG5126   79 DTDGDGKISADEFRRLLTAL---GVSEEEADELFAR----LDTDGDGKISFEEFVAAV 129

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 386763839  91 KLRFAFRIYDMDNDGYISNGELFQVLKMmvgnnLKDTQLQQIVDKTICFADKDEDGKISFDEFCSVV 157
Cdd:cd00051    1 ELREAFRLFDKDGDGTISADELKAALKS-----LGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELM 62

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386763839  25 KRFRKLDLDNSGALSIDEFMSLpeLQQNPLVQRVIDI------FDADGNGEVDFKEFIQG------VSQFSVRGDKLSKL 92
Cdd:NF041410  31 QLFAKLDSDGDGSVSQDELSSA--LSSKSDDGSLIDLselfsdLDSDGDGSLSSDELAAAapppppPPDQAPSTELADDL 108

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 386763839  93 RFAFriyDMDNDGYISNGELfQVLKMMVGNNLKDTQLqqivdkticFA--DKDEDGKISFDEF 153
Cdd:NF041410 109 LSAL---DTDGDGSISSDEL-SAGLTSAGSSADSSQL---------FSalDSDGDGSVSSDEL 158

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386763839  50 QQNPLvQRVIDIFDADGNGEVDFKEFIQGVSQFSvRGDKLSKLRFAFRIYDMDNDGYISNGELFQVLKMM--VGNNLKDT 127
Cdd:NF041410  25 SQQFQ-KQLFAKLDSDGDGSVSQDELSSALSSKS-DDGSLIDLSELFSDLDSDGDGSLSSDELAAAAPPPppPPDQAPST 102

                         90       100       110
                 ....*....|....*....|....*....|....
gi 386763839 128 QLQqivDKTICFADKDEDGKISFDEFCSVVGNTD 161
Cdd:NF041410 103 ELA---DDLLSALDTDGDGSISSDELSAGLTSAG 133

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386763839  20 IRRLGKRFRKLDLDNSGALSIDEFMSLPElqqnPLVQRVIDIFDADGNGEVDFKEFIQGVSQFSVRGDKlSKLRFAFRIY 99
Cdd:COG5126    4 RRKLDRRFDLLDADGDGVLERDDFEALFR----RLWATLFSEADTDGDGRISREEFVAGMESLFEATVE-PFARAAFDLL 78

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 386763839 100 DMDNDGYISNGELFQVLKMMvgnNLKDTQLQQIVDKticfADKDEDGKISFDEFCSVV 157
Cdd:COG5126   79 DTDGDGKISADEFRRLLTAL---GVSEEEADELFAR----LDTDGDGKISFEEFVAAV 129

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 386763839  91 KLRFAFRIYDMDNDGYISNGELFQVLKMmvgnnLKDTQLQQIVDKTICFADKDEDGKISFDEFCSVV 157
Cdd:cd00051    1 ELREAFRLFDKDGDGTISADELKAALKS-----LGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELM 62

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 386763839  27 FRKLDLDNSGALSIdefmslPELQQ-----------NPLVQRVIDIFDADGNGEVDFKEFIqGVSQFsvrgdkLSKLRFA 95
Cdd:cd16180    6 FQAVDRDRSGRISA------KELQRalsngdwtpfsIETVRLMINMFDRDRSGTINFDEFV-GLWKY------IQDWRRL 72

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 386763839  96 FRIYDMDNDGYISNGELFQVLKMMvGNNLKDTQLQQIVDKTicfaDKDEDGKISFDEF----CSVVGNTDIHKK 165
Cdd:cd16180   73 FRRFDRDRSGSIDFNELQNALSSF-GYRLSPQFVQLLVRKF----DRRRRGSISFDDFveacVTLKRLTDAFRK 141

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 386763839   90 SKLRFAFRIYDMDNDGYISNGELFQVLKM-MVGNNLKDTQLQQIVDKticfADKDEDGKISFDEFCSVV 157
Cdd:pfam13499   2 EKLKEAFKLLDSDGDGYLDVEELKKLLRKlEEGEPLSDEEVEELFKE----FDLDKDGRISFEEFLELY 66

EF-hand, calcium binding motif, found in the hexa-EF hand proteins family; The hexa-EF hand proteins family, also named the calbindin sub-family, contains a group of six EF-hand Ca2+-binding proteins, including calretinin (CR, also termed 29 kDa calbindin), calbindin D28K (CB, also termed vitamin D-dependent calcium-binding protein, avian-type), and secretagogin (SCGN). CR is a cytosolic hexa-EF-hand calcium-binding protein predominantly expressed in a variety of normal and tumorigenic t-specific neurons of the central and peripheral nervous system. It is a multifunctional protein implicated in many biological processes, including cell proliferation, differentiation, and cell death. CB is highly expressed in brain tissue. It is a strong calcium-binding and buffering protein responsible for preventing a neuronal death as well as maintaining and controlling calcium homeostasis. SCGN is a six EF-hand calcium-binding protein expressed in neuroendocrine, pancreatic endocrine and retinal cells. It plays a crucial role in cell apoptosis, receptor signaling and differentiation. It is also involved in vesicle secretion through binding to various proteins, including interacts with SNAP25, SNAP23, DOC2alpha, ARFGAP2, rootletin, KIF5B, beta-tubulin, DDAH-2, ATP-synthase and myeloid leukemia factor 2. SCGN functions as a Ca2+ sensor/coincidence detector modulating vesicular exocytosis of neurotransmitters, neuropeptides or hormones. Although the family members share a significant amount of secondary sequence homology, they display altered structural and biochemical characteristics, and operate in distinct fashions. CB contains six EF-hand motifs in a single globular domain, where EF-hands 1, 3, 4, 5 bind four calcium ions. CR contains six EF-hand motifs within two independent domains, CR I-II and CR III-VI. They harbor two and four EF-hand motifs, respectively. The first 5 EF-hand motifs are capable of binding calcium ions, while the EF-hand 6 is inactive. SCGN consists of the three globular domains each of which contains a pair of EF-hand motifs. Human SCGN simultaneously binds four calcium ions through its EF-hands 3, 4, 5 and 6 in one high affinity and three low affinity calcium-binding sites. In contrast, SCGNs in other lower eukaryotes, such as D. rerio, X. laevis, M. domestica, G. gallus, O. anatinus, are fully competent in terms of six calcium-binding.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386763839  25 KRFRKLDLDNSGALSIDE---FMSLPELQQNPLV---------QRVIDIFDADGNGEVDFKEFIQGVS-------QFSVR 85
Cdd:cd15902   94 KIWRKYDTDGSGFIEAKElkgFLKDLLLKNKKHVsppkldeytKLILKEFDANKDGKLELDEMAKLLPvqenfllKFQIL 173

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 386763839  86 GD-KLSKLRF--AFRIYDMDNDGYISNGELFQVLKMMVGNNLKDTQLQQIVDKTIC---FADKDEDGKISFDEFCSVVG 158
Cdd:cd15902  174 GAmDLTKEDFekVFEHYDKDNNGVIEGNELDALLKDLLEKNKADIDKPDLENFRDAilrACDKNKDGKIQKTELALFLS 252

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

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 386763839  11 MCSNFDADEIRRLGKRFRKLDLDNSGALSIDEFMSLPELQQ--NPLVQRVIDIFDADGNGEVDFKEFIQGVSQF 82
Cdd:COG5126   59 MESLFEATVEPFARAAFDLLDTDGDGKISADEFRRLLTALGvsEEEADELFARLDTDGDGKISFEEFVAAVRDY 132

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 386763839  22 RLGKRFRKLDLDNSGALSIDEFMSLPELQQNP-----LVQRVIDIFDADGNGEVDFKEFI----------QGVSQFSVRG 86
Cdd:cd15899  124 KDKKRFEAADQDGDLILTLEEFLAFLHPEESPymldfVIKETLEDLDKNGDGFISLEEFIsdpysadeneEEPEWVKVEK 203

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 386763839  87 DKLSKLRfafriyDMDNDGYISNGELfqvLKMMVGNNlkDTQLQQIVDKTICFADKDEDGKISFDEfcsVVGNTDI 162
Cdd:cd15899  204 ERFVELR------DKDKDGKLDGEEL---LSWVDPSN--QEIALEEAKHLIAESDENKDGKLSPEE---ILDNHEL 265

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 386763839  27 FRKLDLDNSGALSIDEfmslpeLQQnPLV------------QRVIDIFDADGNGEVDFKEFiQGVSQFsvrgdkLSKLRF 94
Cdd:cd16184    6 FQAVDRDRSGKISAKE------LQQ-ALVngnwshfndetcRLMIGMFDKDKSGTIDIYEF-QALWNY------IQQWKQ 71

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 386763839  95 AFRIYDMDNDGYISNGELFQVLKMMvGNNLKDTQLQQIVDKticfADKDEDGKISFDEF 153
Cdd:cd16184   72 VFQQFDRDRSGSIDENELHQALSQM-GYRLSPQFVQFLVSK----YDPRARRSLTLDQF 125

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 386763839  21 RRLGKRFRKLDLDNSGALSIDEFMSLPELQQNPLVQRVIDI----FDADGNGEVDFKEFIQGVSQFSVRGDKLSKLRFA- 95
Cdd:cd16226   35 ERLGIIVDKIDKNGDGFVTEEELKDWIKYVQKKYIREDVDRqwkeYDPNKDGKLSWEEYKKATYGFLDDEEEDDDLHESy 114

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 386763839  96 ----------FRIYDMDNDGYISNGELFQVLKMMVGNNLKDTqlqqIVDKTICFADKDEDGKISFDEF 153
Cdd:cd16226  115 kkmirrderrWKAADQDGDGKLTKEEFTAFLHPEEFPHMRDI----VVQETLEDIDKNKDGFISLEEY 178

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 386763839   22 RLGKRFRKLDLDNSGALSIDEFMSL--PELQQNPL----VQRVIDIFDADGNGEVDFKEFIQGVS 80
Cdd:pfam13499   3 KLKEAFKLLDSDGDGYLDVEELKKLlrKLEEGEPLsdeeVEELFKEFDLDKDGRISFEEFLELYS 67

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386763839  68 GEVDFKEFIQGVSQFSVRGDKLSKlrfAFRIYDMDNDGYISNGELFQVLKMM--VGNNLKDTQLQQIvdktICFADKDED 145
Cdd:cd16251   15 GSFNYKKFFEHVGLKQKSEDQIKK---VFQILDKDKSGFIEEEELKYILKGFsiAGRDLTDEETKAL----LAAGDTDGD 87

                         90
                 ....*....|..
gi 386763839 146 GKISFDEFCSVV 157
Cdd:cd16251   88 GKIGVEEFATLV 99

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 386763839   2 GNETSLPMDMCSNFD-ADEIRRLGKRFRKLDLDNSGALSIDEFMSL--PE---LQQNPLVQRVIDIFDADGNGEVDFKEF 75
Cdd:cd16226   99 GFLDDEEEDDDLHESyKKMIRRDERRWKAADQDGDGKLTKEEFTAFlhPEefpHMRDIVVQETLEDIDKNKDGFISLEEY 178

                 .
gi 386763839  76 I 76
Cdd:cd16226  179 I 179

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 386763839   3 NETSLPMDMCSNFDADEIRRLGKRFRKLDLDNSGALSIDEfmsLPELQQNPLVQRVID-IFDADG--NGEVDFKEFIQGV 79
Cdd:cd21505  203 EELSEELQESNWFSAPSALRVYGQYLNLDKDHNGMLSKQE---LSRYGKGTLTSVFIDrVFQECLtyNGEMDYKTFLDFV 279

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 386763839  80 SQFSVRGDKLSkLRFAFRIYDMDNDGYISNGEL---FQ-VLKMMVGNNLKDTQLQQIVD 134
Cdd:cd21505  280 LAMENRKEPQA-LQYFFRILDLKGQGYLTPFTLnyfFRaIQEKMKEHGQEPVSFEDVKD 337

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 386763839  25 KRFRKLDLDNSGALSIDEFMSL--PE---LQQNPLVQRVIDIFDADGNGEVDFKEFIQGVSQFSVRGDK-----LSKLRF 94
Cdd:cd16224  128 KRFDKANTDGGPGLNLTEFIAFehPEevdYMTEFVIQEALEEHDKDGDGFISLEEFLGDYRKDPTANEDpewiiVEKDRF 207

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 386763839  95 AfRIYDMDNDGYISNGELfqvLKMMVGNNLKDTQLQQIvdKTICFADKDEDGKISFDE 152
Cdd:cd16224  208 V-NDYDKDNDGKLDPQEL---LPWVVPNNYGIAQEEAL--HLIDEMDLNGDGRLSEEE 259

EF-hand, calcium binding motif, found in uncharacterized calglandulin-like proteins; The family corresponds to a group of uncharacterized calglandulin-like proteins. Although their biological function remain unclear, they show high sequence similarity with human calglandulin-like protein GAGLP, which is an ortholog of calglandulin from the venom glands of Bothrops insularis snake. Both GAGLP and calglandulin are putative Ca2+-binding proteins with four EF-hand motifs. However, members in this family contain only three EF-hand motifs. In this point, they may belong to the parvalbumin-like EF-hand family, which is characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix).

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386763839  68 GEVDFKEFIQGVSQFSVRGDKLSKLRFAFRIYDMDNDGYISNGELFQVLKMMVGNN----LKDTQLQQIVDKticfADKD 143
Cdd:cd16252   15 GSFNYSKFFEYMQKFQTSEQQEEAIRKAFQMLDKDKSGFIEWNEIKYILSTVPSSMpvapLSDEEAEAMIQA----ADTD 90

                         90
                 ....*....|....
gi 386763839 144 EDGKISFDEFCSVV 157
Cdd:cd16252   91 GDGRIDFQEFSDMV 104

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 386763839  27 FRKLDLDNSGALSIDEFMSLpeLQQ------NPLVQRVIDIFDADGNGEVDFKEFIQGVSQFSVRGDklskLRFAFRIYD 100
Cdd:cd15898    6 WIKADKDGDGKLSLKEIKKL--LKRlnirvsEKELKKLFKEVDTNGDGTLTFDEFEELYKSLTERPE----LEPIFKKYA 79

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 386763839 101 MDNDGYISNGELFQVLKMMVGNNLKDTQLQQIVDKticFADKDEDGKISFDEFCS 155
Cdd:cd15898   80 GTNRDYMTLEEFIRFLREEQGENVSEEECEELIEK---YEPERENRQLSFEGFTN 131

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 386763839  20 IRRLGKRFRKLDLDNSGALSIDE--------FMSLPELQQNplvQRVIDIfDADGNGEVDFKEFIQgvSQFSVRGDKLSK 91
Cdd:cd16227   35 KRRLAVLAKKMDLNDDGFIDRKElkawilrsFKMLDEEEAN---ERFEEA-DEDGDGKVTWEEYLA--DSFGYDDEDNEE 108

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 386763839  92 LRFA---------------FRIYDMDNDGYISNGELfqvLKMMVGNNLKDtQLQQIVDKTICFADKDEDGKISFDEF 153
Cdd:cd16227  109 MIKDsteddlklleddkemFEAADLNKDGKLDKTEF---SAFQHPEEYPH-MHPVLIEQTLRDKDKDNDGFISFQEF 181

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 386763839  27 FRKLDLDNSGALSIDEFMS-LPELQQN---PLVQRVIDIFDADGNGEVDFKEFIQ-GVSqfsvrgdkLSKLRFAFRIYDM 101
Cdd:cd16180   73 FRRFDRDRSGSIDFNELQNaLSSFGYRlspQFVQLLVRKFDRRRRGSISFDDFVEaCVT--------LKRLTDAFRKYDT 144

                 ....*.
gi 386763839 102 DNDGYI 107
Cdd:cd16180  145 NRTGYA 150

EF-hand, calcium binding motif, found in the hexa-EF hand proteins family; The hexa-EF hand proteins family, also named the calbindin sub-family, contains a group of six EF-hand Ca2+-binding proteins, including calretinin (CR, also termed 29 kDa calbindin), calbindin D28K (CB, also termed vitamin D-dependent calcium-binding protein, avian-type), and secretagogin (SCGN). CR is a cytosolic hexa-EF-hand calcium-binding protein predominantly expressed in a variety of normal and tumorigenic t-specific neurons of the central and peripheral nervous system. It is a multifunctional protein implicated in many biological processes, including cell proliferation, differentiation, and cell death. CB is highly expressed in brain tissue. It is a strong calcium-binding and buffering protein responsible for preventing a neuronal death as well as maintaining and controlling calcium homeostasis. SCGN is a six EF-hand calcium-binding protein expressed in neuroendocrine, pancreatic endocrine and retinal cells. It plays a crucial role in cell apoptosis, receptor signaling and differentiation. It is also involved in vesicle secretion through binding to various proteins, including interacts with SNAP25, SNAP23, DOC2alpha, ARFGAP2, rootletin, KIF5B, beta-tubulin, DDAH-2, ATP-synthase and myeloid leukemia factor 2. SCGN functions as a Ca2+ sensor/coincidence detector modulating vesicular exocytosis of neurotransmitters, neuropeptides or hormones. Although the family members share a significant amount of secondary sequence homology, they display altered structural and biochemical characteristics, and operate in distinct fashions. CB contains six EF-hand motifs in a single globular domain, where EF-hands 1, 3, 4, 5 bind four calcium ions. CR contains six EF-hand motifs within two independent domains, CR I-II and CR III-VI. They harbor two and four EF-hand motifs, respectively. The first 5 EF-hand motifs are capable of binding calcium ions, while the EF-hand 6 is inactive. SCGN consists of the three globular domains each of which contains a pair of EF-hand motifs. Human SCGN simultaneously binds four calcium ions through its EF-hands 3, 4, 5 and 6 in one high affinity and three low affinity calcium-binding sites. In contrast, SCGNs in other lower eukaryotes, such as D. rerio, X. laevis, M. domestica, G. gallus, O. anatinus, are fully competent in terms of six calcium-binding.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 386763839  96 FRIYDMDNDGYISNGEL---FQ-VLKMMVGNNLKDTQLQQIVDKTICFADKDEDGKISFDEF 153
Cdd:cd15902    5 WMHFDADGNGYIEGKELdsfLReLLKALNGKDKTDDEVAEKKKEFMEKYDENEDGKIEIREL 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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386763839  16 DADEIRRLGKRFRKLDLDNSGALSIDEFMSLpelqqnplvqrvIDIFDADGNGEVDFKEFIQGVSqfsvrgdKLSKLRFA 95
Cdd:cd16182   17 DAVELQKLLNASLLKDMPKFDGFSLETCRSL------------IALMDTNGSGRLDLEEFKTLWS-------DLKKWQAI 77

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 386763839  96 FRIYDMDNDGYISNGELFQVLK---MMVGNNLkdtqLQQIVDKticFADKdeDGKISFDEFCSVV 157
Cdd:cd16182   78 FKKFDTDRSGTLSSYELRKALEsagFHLSNKV----LQALVLR---YADS--TGRITFEDFVSCL 133

EF-hand, calcium binding motif, found in calbindin (CB); CB, also termed calbindin D28, or D-28K, or avian-type vitamin D-dependent calcium-binding protein, is a unique intracellular calcium binding protein that functions as both a calcium sensor and buffer in eukaryotic cells, which undergoes a conformational change upon calcium binding and protects cells against insults of high intracellular calcium concentration. CB is highly expressed in brain and sensory neurons. It plays essential roles in neural functioning, altering synaptic interactions in the hippocampus, modulating calcium channel activity, calcium transients, and intrinsic neuronal firing activity. It prevents a neuronal death, as well as maintains and controls calcium homeostasis. CB also modulates the activity of proteins participating in the development of neurodegenerative disorders such as Alzheimer's disease, Huntington's disease, and bipolar disorder. Moreover, CB interacts with Ran-binding protein M, a protein known to involve in microtubule function. It also interacts with alkaline phosphatase and myo-inositol monophosphatase, as well as caspase 3, an enzyme that plays an important role in the regulation of apoptosis. CB contains six EF-hand motifs in a single globular domain, where EF-hands 1, 3, 4, 5 bind four calcium ions with high affinity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386763839  25 KRFRKLDLDNSGALSIDEFMSL------------PELQQNPLVQRVIDIFDADGNGEVDFKEF-----IQGVSQFSVRGD 87
Cdd:cd16176   89 QTWRKYDADHSGFIEADELKSFlkdllkkankpfDESKLEEYTHTMLKMFDSNNDGKLGLTEMarllpVQENFLLKFQGV 168

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 386763839  88 KLSKLRF--AFRIYDMDNDGYISNGELFQVLKMMVGNNLKDTQLQQI 132
Cdd:cd16176  169 KMCGKEFnkIFELYDQDGNGYIDENELDALLKDLCEKNKKDLDINNI 215

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 386763839  21 RRLGKRFRKLDLDNSGALSIDEFMSLPELQQNPL----VQRVIDIFDADGNGEVDFKEFIQGVSQFSVRGDK-------- 88
Cdd:cd15899   35 RRLGVIVSKMDVDKDGFISAKELHSWILESFKRHameeSKEQFRAVDPDEDGHVSWDEYKNDTYGSVGDDEEnvadnike 114

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386763839  89 -------LSKLRFAFRIYDMDNDGYISNGELFQVLKMMVGNNLKDTQLQQIVDKTicfaDKDEDGKISFDEFCSVVGNTD 161
Cdd:cd15899  115 deeykklLLKDKKRFEAADQDGDLILTLEEFLAFLHPEESPYMLDFVIKETLEDL----DKNGDGFISLEEFISDPYSAD 190

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 386763839   91 KLRFAFRIYDMDNDGYISNGELFQVLKMM 119
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELLKKL 29

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 386763839    91 KLRFAFRIYDMDNDGYISNGELFQVLKMM 119
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29