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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15228547   5 RVFEKFDKNKDGKLSLDEFREVALAfspyftqeDIVKFFEEIDVDGNGELNADEFTSC--------IEKMLKEVFVFCDV 76
Cdd:COG5126   9 RRFDLLDADGDGVLERDDFEALFRR--------LWATLFSEADTDGDGRISREEFVAGmeslfeatVEPFARAAFDLLDT 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|.
gi 15228547  77 DGDGKIPASESYVTMTSLGkkFTEETSAEKVRAADVDGDGYLNFDEFMALV 127
Cdd:COG5126  81 DGDGKISADEFRRLLTALG--VSEEEADELFARLDTDGDGKISFEEFVAAV 129

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15228547   5 RVFEKFDKNKDGKLSLDEFREVALAfspyftqeDIVKFFEEIDVDGNGELNADEFTSC--------IEKMLKEVFVFCDV 76
Cdd:COG5126   9 RRFDLLDADGDGVLERDDFEALFRR--------LWATLFSEADTDGDGRISREEFVAGmeslfeatVEPFARAAFDLLDT 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|.
gi 15228547  77 DGDGKIPASESYVTMTSLGkkFTEETSAEKVRAADVDGDGYLNFDEFMALV 127
Cdd:COG5126  81 DGDGKISADEFRRLLTALG--VSEEEADELFARLDTDGDGKISFEEFVAAV 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
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 15228547   3 AKRVFEKFDKNKDGKLSLDEFREVALAFSPYFTQEDIVKFFEEIDVDGNGELNADEF 59
Cdd:cd00051   2 LREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEF 58

EF-hand domain pair;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 15228547     3 AKRVFEKFDKNKDGKLSLDEFREVALAFSPY--FTQEDIVKFFEEIDVDGNGELNADEF 59
Cdd:pfam13499   4 LKEAFKLLDSDGDGYLDVEELKKLLRKLEEGepLSDEEVEELFKEFDLDKDGRISFEEF 62

Eps15 homology domain; Pair of EF hand motifs that recognise proteins containing Asn-Pro-Phe (NPF) sequences.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 15228547      6 VFEKFDKNKDGKLSLDEFREVALAFSpyFTQEDIVKFFEEIDVDGNGELNADEF 59
Cdd:smart00027  15 IFRSLDKNQDGTVTGAQAKPILLKSG--LPQTLLAKIWNLADIDNDGELDKDEF 66

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15228547   5 RVFEKFDKNKDGKLSLDEFREVALAfspyftqeDIVKFFEEIDVDGNGELNADEFTSC--------IEKMLKEVFVFCDV 76
Cdd:COG5126   9 RRFDLLDADGDGVLERDDFEALFRR--------LWATLFSEADTDGDGRISREEFVAGmeslfeatVEPFARAAFDLLDT 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|.
gi 15228547  77 DGDGKIPASESYVTMTSLGkkFTEETSAEKVRAADVDGDGYLNFDEFMALV 127
Cdd:COG5126  81 DGDGKISADEFRRLLTALG--VSEEEADELFARLDTDGDGKISFEEFVAAV 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
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 15228547   3 AKRVFEKFDKNKDGKLSLDEFREVALAFSPYFTQEDIVKFFEEIDVDGNGELNADEF 59
Cdd:cd00051   2 LREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEF 58

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15228547    4 KRVFEKFDKNKDGKLSLDEFREVALAFSPYFTQEDIVKFFEEIDVDGNGELNADEFTSCIEKM------------LKEVF 71
Cdd:NF041410  30 KQLFAKLDSDGDGSVSQDELSSALSSKSDDGSLIDLSELFSDLDSDGDGSLSSDELAAAAPPPppppdqapstelADDLL 109

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 15228547   72 VFCDVDGDGKIPASEsyvtMTSLGKKFTEETSAEKVRAA-DVDGDGYLNFDEFMA 125
Cdd:NF041410 110 SALDTDGDGSISSDE----LSAGLTSAGSSADSSQLFSAlDSDGDGSVSSDELAA 160

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 15228547   7 FEKFDKNKDGKLSLDEFREVALAFSPYFTQEDIVKFFEEIDVDGNGELNADEFTSC---IEKMlKEVFVFCDVDGDGKIP 83
Cdd:cd16185   6 FRAVDRDRSGSIDVNELQKALAGGGLLFSLATAEKLIRMFDRDGNGTIDFEEFAALhqfLSNM-QNGFEQRDTSRSGRLD 84

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*
gi 15228547  84 ASESYVTMTSLGKKFTEETSAEKVRAADVDGDGYLNFDEFMALVI 128
Cdd:cd16185  85 ANEVHEALAASGFQLDPPAFQALFRKFDPDRGGSLGFDDYIELCI 129

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

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 15228547   3 AKRVFEKFDKNKDGKLSLDEFREVALAFSpyFTQEDIVKFFEEIDVDGNGELNADEF 59
Cdd:COG5126  71 ARAAFDLLDTDGDGKISADEFRRLLTALG--VSEEEADELFARLDTDGDGKISFEEF 125

EF-hand domain pair;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 15228547     3 AKRVFEKFDKNKDGKLSLDEFREVALAFSPY--FTQEDIVKFFEEIDVDGNGELNADEF 59
Cdd:pfam13499   4 LKEAFKLLDSDGDGYLDVEELKKLLRKLEEGepLSDEEVEELFKEFDLDKDGRISFEEF 62

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 15228547   4 KRVFEKFDKNKDGKLSLDEFrevaLAF-----SPYFTQEDIVKFFEEIDVDGNGELNADEFTS------------CIEKM 66
Cdd:cd15899 126 KKRFEAADQDGDLILTLEEF----LAFlhpeeSPYMLDFVIKETLEDLDKNGDGFISLEEFISdpysadeneeepEWVKV 201

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 15228547  67 LKEVFV-FCDVDGDGKIPASESYVTMTSLGKKFTEETSAEKVRAADVDGDGYLNFDE 122
Cdd:cd15899 202 EKERFVeLRDKDKDGKLDGEELLSWVDPSNQEIALEEAKHLIAESDENKDGKLSPEE 258

phosphatidylserine decarboxylase

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 15228547    3 AKRVFEKFDKNKDGKLSLDEFREVALAFSPYFTQEDIVKFFEEIDVDGNGELNADEFT 60
Cdd:PLN02964 181 ARRILAIVDYDEDGQLSFSEFSDLIKAFGNLVAANKKEELFKAADLNGDGVVTIDELA 238

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 15228547   4 KRVFEKFDKNKDGKLSLDEFREVA----------LAFSPYFTQEDIVKFFEEIDVDGNGELNADEFTSCIEKML------ 67
Cdd:cd15902  47 KEFMEKYDENEDGKIEIRELANILpteenflllfRREQPLISSVEFMKIWRKYDTDGSGFIEAKELKGFLKDLLlknkkh 126

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15228547  68 ----------KEVFVFCDVDGDGKIPASE-----------SYVTMTSLGKKFTEETSAEKVRAADVDGDGYLNFDEFMAL 126
Cdd:cd15902 127 vsppkldeytKLILKEFDANKDGKLELDEmakllpvqenfLLKFQILGAMDLTKEDFEKVFEHYDKDNNGVIEGNELDAL 206

                .
gi 15228547 127 V 127
Cdd:cd15902 207 L 207

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 15228547   4 KRVFEKFDKNKDGKLSLDEFREVALAFSPYFTQEDIVKFFEEIDVDGNGELNADEFtsciekmLKEVFVFCDVDGDGKIP 83
Cdd:cd16226  38 GIIVDKIDKNGDGFVTEEELKDWIKYVQKKYIREDVDRQWKEYDPNKDGKLSWEEY-------KKATYGFLDDEEEDDDL 110

                        90       100       110       120
                ....*....|....*....|....*....|....*....|..
gi 15228547  84 aSESYVTMTSLGKKfteetsaeKVRAADVDGDGYLNFDEFMA 125
Cdd:cd16226 111 -HESYKKMIRRDER--------RWKAADQDGDGKLTKEEFTA 143

EF-hand, calcium binding motif, found in secretagogin (SCGN); 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 calcium sensor/coincidence detector modulating vesicular exocytosis of neurotransmitters, neuropeptides or hormones. It also serves as a calcium buffer in neurons. Thus, SCGN may be linked to the pathogenesis of neurological diseases such as Alzheimer's, and also acts as a serum marker of neuronal damage, or as a tumor biomarker. SCGN consists of the three globular domains each of which contains a pair of EF-hand motifs. All six EF hand motifs of SCGN in some eukaryotes, including D. rerio, X. laevis, M. domestica, G. gallus, O. anatinus, could potentially bind six calcium ions. In contrast, SCGNs from higher eukaryotes have at least one non-functional EF-hand motif due to the mutation(s) or deletions. For instance, the EF1 loop does not coordinate calcium ion due to the key residue asparagine replaced by lysine in SCGNs of many mammalian species. Moreover, the EF2 loop seems to be competent for calcium-binding in most mammalian SCGNs except for human and chimpanzee orthologs.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15228547  10 FDKNKDGKLSLDEF-REVAL-----------AFSPYFTQEDIVKFFEEIDVDGNGELNADEF----------------TS 61
Cdd:cd16178 145 FDKNKDGRLDLNDMaRILALqenfllqfkmdAMSEEERKRDFEKIFAHYDVSKTGALEGPEVdgfvkdmmelvkpsisGV 224

                        90       100
                ....*....|....*....|....*
gi 15228547  62 CIEKMLKEVFVFCDVDGDGKIPASE 86
Cdd:cd16178 225 QLDKFKEIILNHCDVNKDGKIQKSE 249

EF-hand, extracellular calcium-binding (EC) motif, found in secreted protein acidic and rich in cysteine (SPARC)-like proteins; The SPARC protein family represents a diverse group of proteins that share a follistatin-like (FS) domain and an extracellular calcium-binding (EC) domain with two EF-hand motifs. It includes SPARC (for secreted protein acidic and rich in cysteine, also termed osteonectin/ON, or basement-membrane protein 40/BM-40), SPARC-like protein 1 (for secreted protein, acidic and rich in cysteines-like 1/ SPARCL1, also termed high endothelial venule protein/Hevi, or MAST 9, or SC-1, or RAGS-1, or QR1, or ECM 2), testicans 1, 2, and 3 (also termed SPARC/osteonectin, CWCV, and Kazal-like domains proteoglycans, or SPOCK), secreted modular calcium-binding protein SMOC-1 (also termed SPARC-related modular calcium-binding protein 1) and SMOC-2 (also termed SPARC-related modular calcium-binding protein 2, or smooth muscle-associated protein 2/SMAP-2), follistatin-related protein 1 (FRP-1, also termed follistatin-like protein 1/fstl-1, TSC-36/Flik, TGF-beta inducible protein). The SPARC proteins have been implicated in modulating cell interaction with the extracellular milieu, including regulation of extracellular matrix assembly and deposition, counter-adhesion, effects on extracellular protease activity, and modulation of growth factor/cytokine signaling pathways, as well as in development and disease.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 15228547   2 SAKRVFEKFDKNKDGKLSLDEFREVALAFSPYftQEDIVKFFEEIDVDGNGELNADEFTSC 62
Cdd:cd00252  46 IAQWEFDNLDNNKDGKLDKRELAPFRAPLMPL--EHCARGFFESCDLNKDKKISLQEWLGC 104

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 15228547   4 KRVFEKFDKNKDGKLSLDEFREVALAFSPYFTQEDIVKFFEEIDVDGNGELNADEFtscIEKMLKEVFVFCDVDGDGKIP 83
Cdd:cd15899  38 GVIVSKMDVDKDGFISAKELHSWILESFKRHAMEESKEQFRAVDPDEDGHVSWDEY---KNDTYGSVGDDEENVADNIKE 114

                        90       100       110       120
                ....*....|....*....|....*....|....*....|..
gi 15228547  84 ASESYVTMTSLGKKFteetsaekvRAADVDGDGYLNFDEFMA 125
Cdd:cd15899 115 DEEYKKLLLKDKKRF---------EAADQDGDLILTLEEFLA 147

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 15228547   8 EKFDKNKDGKLSLDEFRE---VALAFSPYF--------TQEDIVKFFEEIDVDGNGELNADE----FTSCIEKMLKE--- 69
Cdd:cd15902 141 KEFDANKDGKLELDEMAKllpVQENFLLKFqilgamdlTKEDFEKVFEHYDKDNNGVIEGNEldalLKDLLEKNKADidk 220

                        90       100
                ....*....|....*....|....*.
gi 15228547  70 ---------VFVFCDVDGDGKIPASE 86
Cdd:cd15902 221 pdlenfrdaILRACDKNKDGKIQKTE 246

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 15228547   5 RVFEKFDKnKDGKLSLDEFRE-----VALAFSPYFTQEDIVKFFEEIDVDGNGELNADEFTSCIEKML--KEVFVFCDVD 77
Cdd:cd15897   4 NVFQAVAG-DDGEISATELQQalsnvGWTHFDLGFSLETCRSMIAMMDRDHSGKLNFSEFKGLWNYIKawQEIFRTYDTD 82

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|.
gi 15228547  78 GDGKIPASESYVTMTSLGKKFTEETSAEKVRAADvDGDGYLNFDEFMALVI 128
Cdd:cd15897  83 GSGTIDSNELRQALSGAGYRLSEQTYDIIIRRYD-RGRGNIDFDDFIQCCV 132

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 15228547   1 MSAKRVFEKFDKNKDGKLSLDEFR------------EVALAFSPYF-------TQEDIVKF---FEEIDVDGNGELNADE 58
Cdd:cd16225  73 EENEQIFKAVDTDKDGNVSWEEYRvhfllskgyseeEAEEKIKNNEelkldedDKEVLDRYkdrWSQADEPEDGLLDVEE 152

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15228547  59 FTS---------CIEKMLKEVFVFCDVDGDGKIPASE----SYVTMTSLGKKFTEETSAEKVR----AADVDGDGYLNFD 121
Cdd:cd16225 153 FLSfrhpehsrgMLKNMVKEILHDLDQDGDEKLTLDEfvslPPGTVEEQQAEDDDEWKKERKKefeeVIDLNHDGKVTKE 232

                ...
gi 15228547 122 EFM 124
Cdd:cd16225 233 ELE 235

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 15228547   4 KRVFEKFDKNKDGKLSLDE----FREVALAFSPYFTQEDIVKFfeeiDVDGNGELNADEF-TSCIE-KMLKEVFVFCDVD 77
Cdd:cd16184  70 KQVFQQFDRDRSGSIDENElhqaLSQMGYRLSPQFVQFLVSKY----DPRARRSLTLDQFiQVCVQlQSLTDAFRQRDTQ 145

                        90
                ....*....|....*.
gi 15228547  78 GDGKIPAS-ESYVTMT 92
Cdd:cd16184 146 MTGTITISyEDFLTMA 161

Eps15 homology domain; Pair of EF hand motifs that recognise proteins containing Asn-Pro-Phe (NPF) sequences.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 15228547      6 VFEKFDKNKDGKLSLDEFREVALAFSpyFTQEDIVKFFEEIDVDGNGELNADEF 59
Cdd:smart00027  15 IFRSLDKNQDGTVTGAQAKPILLKSG--LPQTLLAKIWNLADIDNDGELDKDEF 66

phosphatidylserine decarboxylase

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 15228547   68 KEVFVFCDVDGDGKIPASESYVTMTSLGKKFTEETSAEKVRAADVDGDGYLNFDEFMALV 127
Cdd:PLN02964 182 RRILAIVDYDEDGQLSFSEFSDLIKAFGNLVAANKKEELFKAADLNGDGVVTIDELAALL 241

EF-hand motif found in phosphoinositide phospholipase C eta 2 (PI-PLC-eta2); PI-PLC-eta2, also termed 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-2, or phosphoinositide phospholipase C-like 4, or phospholipase C-like protein 4 (PLC-L4), or phospholipase C-eta-2 (PLC-eta2), is a neuron-specific PI-PLC that is most abundant in the brain, particularly in the hippocampus, habenula, olfactory bulb, cerebellum, and throughout the cerebral cortex. It is also expressed in the pituitary gland, pineal gland, retina, and lung, as well as in neuroendocrine cells. PI-PLC-eta2 has been implicated in the regulation of neuronal differentiation/maturation. It is required for retinoic acid-stimulated neurite growth. It may also in part function downstream of G-protein-coupled receptors and play an important role in the formation and maintenance of the neuronal network in the postnatal brain. Moreover, PI-PLC-eta2 acts as a Ca2+ sensor that shows a canonical EF-loop directing Ca2+-sensitivity and thus can amplify transient Ca2+ signals. Its activation can be triggered either by intracellular calcium mobilization or by G beta-gamma signaling. PI-PLC-eta2 contains an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core domain, a C2 domain, and a unique C-terminal tail that terminates with a PDZ-binding motif, a potential interaction site for other signaling proteins. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. The C-terminal tail harbors a number of proline-rich motifs which may interact with SH3 (Src homology 3) domain-containing proteins, as well as many serine/threonine residues, suggesting possible regulation of interactions by protein kinases/phosphatases.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 15228547   2 SAKRVFEKFDKNKDGKLSLDEFREVALAFSPYFTQEDIVKFFEEIDVDGN-GELNADEFTSCIEKM 66
Cdd:cd16221   1 WLKQTFDEADKNGDGSLSIGEVLQLLHKLNVNLPRQKVKQMFKEADTDDNqGTLGFEEFCAFYKMM 66

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 15228547   1 MSAKRVFEKFDKNKDGKLSLDEFREvALAFSPYFTQEDIVK-FFEEIDVDGNGELNADEFTS-CIE-KMLKEVFVFCDVD 77
Cdd:cd16185  66 SNMQNGFEQRDTSRSGRLDANEVHE-ALAASGFQLDPPAFQaLFRKFDPDRGGSLGFDDYIElCIFlASARNLFQAFDRQ 144

                ....*
gi 15228547  78 GDGKI 82
Cdd:cd16185 145 RTGRV 149

EF-hand motif found in phosphoinositide phospholipase C delta 4 (PI-PLC-delta4); PI-PLC-delta4, also termed 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-4 (PLCD4), or phospholipase C-delta-4 (PLC-delta-4), is expressed in various tissues with the highest levels detected selectively in the brain, skeletal muscle, testis and kidney. It plays a significant role in cell growth, cell proliferation, tumorigenesis, and in an early stage of fertilization. PI-PLC-delta4 may function as a key enzyme in the regulation of PtdIns(4,5)P2 levels and Ca2+ metabolism in nuclei in response to growth factors, and its expression may be partially regulated by an increase in cytoplasmic Ca2+. Moreover, PI-PLC-delta4 binds glutamate receptor-interacting protein1 (GRIP1) in testis and is required for calcium mobilization essential for the zona pellucida-induced acrosome reaction in sperm. Overexpression or dysregulated expression of PLCdelta4 may initiate oncogenesis in certain tissues through upregulating erbB1/2 expression, extracellular signal-regulated kinase (ERK) signaling pathway, and proliferation in MCF-7 cells. PI-PLC-delta4 contains an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core domain, and a 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. Unlike PI-PLC-delta 1 and 3, a putative nuclear export sequence (NES) located in the EF-hand domain, which may be responsible transporting PI-PLC-delta1 and 3 from the cell nucleus, is not present in PI-PLC-delta4.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 15228547   7 FEKFDKNKDGKLSLDEFREVALAFSPYFTQEDIVKFFEEIDVDGNGELNADEFTScIEKMLKE----VFVFCDVDGDGK 81
Cdd:cd16219   6 FQKADKNKDGRMNFKEVRDLLKMMNVDMNEEHALRLFQMADKSESGTLEGEEFVL-FYKALTQredvLKIFQDFSADGQ 83

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 15228547   4 KRVFEKFDKNKDGKLSLDEFrevaLAFS-----PYFTQEDIVKFFEEIDVDGNGELNADEFTScIEKMLKEVFV------ 72
Cdd:cd16227 125 KEMFEAADLNKDGKLDKTEF----SAFQhpeeyPHMHPVLIEQTLRDKDKDNDGFISFQEFLG-DRAGHEDKEWllvekd 199

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 15228547  73 ----FCDVDGDGKIPASE--SYVTMTSlgkkftEETSAEKVR----AADVDGDGYLNFDE 122
Cdd:cd16227 200 rfdeDYDKDGDGKLDGEEilSWLVPDN------EEIAEEEVDhlfaSADDDHDDRLSFDE 253

EF-hand domain;

                          10        20
                  ....*....|....*....|...
gi 15228547     4 KRVFEKFDKNKDGKLSLDEFREV 26
Cdd:pfam13405   3 REAFKLFDKDGDGKISLEELRKA 25

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
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 15228547  67 LKEVFVFCDVDGDGKIPASESYVTMTSLGKKFTEETSAEKVRAADVDGDGYLNFDEFM 124
Cdd:cd16202   2 LKDQFRKADKNGDGKLSFKECKKLLKKLNVKVDKDYAKKLFQEADTSGEDVLDEEEFV 59

EF-hand domain pair;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 15228547    78 GDGKIPASESYVTMTSLGKK-FTEETSAEKVRAADVDGDGYLNFDEFMALV 127
Cdd:pfam13833   1 EKGVITREELKRALALLGLKdLSEDEVDILFREFDTDGDGYISFDEFCVLL 51

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 15228547   4 KRVFEKFDKNKDGKLSLDEFREVALAF----SPYFTQEDIVKFfeeidVDGNGELNADEFTSCIEKM--LKEVFVFCDVD 77
Cdd:cd15897  73 QEIFRTYDTDGSGTIDSNELRQALSGAgyrlSEQTYDIIIRRY-----DRGRGNIDFDDFIQCCVRLqrLTDAFRRYDKD 147

                        90
                ....*....|....*.
gi 15228547  78 GDGKIPAS-ESYVTMT 92
Cdd:cd15897 148 QDGQIQVNyDEFLQGT 163

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 15228547      4 KRVFEKFDKNKDGKLSLDEFREV 26
Cdd:smart00054   3 KEAFRLFDKDGDGKIDFEEFKDL 25