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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1063722196  25 QFFRAMDVNGDGRVSLQEYTDFLRQTAGLAWIHPEMFRELDRNGDGQLDFWEVLTL 80
Cdd:COG5126    73 AAFDLLDTDGDGKISADEFRRLLTALGVSEEEADELFARLDTDGDGKISFEEFVAA 128

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1063722196  25 QFFRAMDVNGDGRVSLQEYTDFLRQTAGLAWIHPEMFRELDRNGDGQLDFWEVLTL 80
Cdd:COG5126    73 AAFDLLDTDGDGKISADEFRRLLTALGVSEEEADELFARLDTDGDGKISFEEFVAA 128

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1063722196  25 QFFRAMDVNGDGRVSLQEYTDFLRQTAGLAWIHPE----MFRELDRNGDGQLDFWEVLTLYY 82
Cdd:pfam13499   6 EAFKLLDSDGDGYLDVEELKKLLRKLEEGEPLSDEeveeLFKEFDLDKDGRISFEEFLELYS 67

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
                   ....*....|....*.
gi 1063722196   59 EMFRELDRNGDGQLDF 74
Cdd:smart00054   4 EAFRLFDKDGDGKIDF 19

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1063722196  25 QFFRAMDVNGDGRVSLQEYTDFLRQTAGLAWIHPEMFRELDRNGDGQLDFWEVLTL 80
Cdd:COG5126    73 AAFDLLDTDGDGKISADEFRRLLTALGVSEEEADELFARLDTDGDGKISFEEFVAA 128

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1063722196  25 QFFRAMDVNGDGRVSLQEYTDFLRQTAGLAWIHPE----MFRELDRNGDGQLDFWEVLTLYY 82
Cdd:pfam13499   6 EAFKLLDSDGDGYLDVEELKKLLRKLEEGEPLSDEeveeLFKEFDLDKDGRISFEEFLELYS 67

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1063722196  27 FRAMDVNGDGRVSLQEYTDFLrqtaglawiHPEMF------------RELDRNGDGQLDFWEVLTLYY 82
Cdd:cd15899   129 FEAADQDGDLILTLEEFLAFL---------HPEESpymldfviketlEDLDKNGDGFISLEEFISDPY 187

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1063722196  27 FRAMDVNGDGRVSLQEYTDFLrqtaglawiHPEMF------------RELDRNGDGQLDFWE 76
Cdd:cd16226   125 WKAADQDGDGKLTKEEFTAFL---------HPEEFphmrdivvqetlEDIDKNKDGFISLEE 177

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
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1063722196  30 MDVNGDGRVSLQEY-TDFLRQ---TAGLAWIHPE--MFRE-LDRNGDGQLDFWEV 77
Cdd:cd16226   165 IDKNKDGFISLEEYiGDMYRDddeEEDPDWVKSEreQFKEfRDKNKDGKMDREEV 219

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1063722196  26 FFRAMDVNGDGRVSLQEYTdflrqtaglAWIHPE----MF--------RELDRNGDGQLDFWEVL 78
Cdd:cd16227   127 MFEAADLNKDGKLDKTEFS---------AFQHPEeyphMHpvlieqtlRDKDKDNDGFISFQEFL 182

EF-hand, calcium binding motif, found in reticulocalbin-3 (RCN-3); RCN-3, also termed EF-hand calcium-binding protein RLP49, 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 His-Asp-Glu-Leu (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
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1063722196  30 MDVNGDGRVSLQEY-TDFLRQTAGL---AWIHPE--MFREL-DRNGDGQLDFWEV 77
Cdd:cd16230   169 LDKNKDGYVQVEEYiADLYSGEPGEeepAWVQTErqQFRQFrDLNKDGRLDGSEV 223

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 1063722196  59 EMFRELDRNGDGQLDFWEVLTL 80
Cdd:pfam00036   4 EIFRLFDKDGDGKIDFEEFKEL 25

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1063722196  25 QFFRAMDVNGDGRVSLQEytdFLRQTAGL---AWIHPEMFR---ELDRNGDGQLDFWEVL 78
Cdd:cd16227   163 QTLRDKDKDNDGFISFQE---FLGDRAGHedkEWLLVEKDRfdeDYDKDGDGKLDGEEIL 219

EF-hand domain pair;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 1063722196   2 DELHEAAIAYYNNGSMEQQNLSwQFFRAMDVNGDGRVSLQEYTDFLR 48
Cdd:pfam13499  22 EELKKLLRKLEEGEPLSDEEVE-ELFKEFDLDKDGRISFEEFLELYS 67

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

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 1063722196   2 DELHEAAIAYYNNGSMEQQNlswQFFRAMDVNGDGRVSLQEYTDFLR 48
Cdd:cd00051    20 DELKAALKSLGEGLSEEEID---EMIREVDKDGDGKIDFEEFLELMA 63

S-100: S-100 domain, which represents the largest family within the superfamily of proteins carrying the Ca-binding EF-hand motif. Note that this S-100 hierarchy contains only S-100 EF-hand domains, other EF-hands have been modeled separately. S100 proteins are expressed exclusively in vertebrates, and are implicated in intracellular and extracellular regulatory activities. Intracellularly, S100 proteins act as Ca-signaling or Ca-buffering proteins. The most unusual characteristic of certain S100 proteins is their occurrence in extracellular space, where they act in a cytokine-like manner through RAGE, the receptor for advanced glycation products. Structural data suggest that many S100 members exist within cells as homo- or heterodimers and even oligomers; oligomerization contributes to their functional diversification. Upon binding calcium, most S100 proteins change conformation to a more open structure exposing a hydrophobic cleft. This hydrophobic surface represents the interaction site of S100 proteins with their target proteins. There is experimental evidence showing that many S100 proteins have multiple binding partners with diverse mode of interaction with different targets. In addition to S100 proteins (such as S100A1,-3,-4,-6,-7,-10,-11,and -13), this group includes the ''fused'' gene family, a group of calcium binding S100-related proteins. The ''fused'' gene family includes multifunctional epidermal differentiation proteins - profilaggrin, trichohyalin, repetin, hornerin, and cornulin; functionally these proteins are associated with keratin intermediate filaments and partially crosslinked to the cell envelope. These ''fused'' gene proteins contain N-terminal sequence with two Ca-binding EF-hands motif, which may be associated with calcium signaling in epidermal cells and autoprocessing in a calcium-dependent manner. In contrast to S100 proteins, "fused" gene family proteins contain an extraordinary high number of almost perfect peptide repeats with regular array of polar and charged residues similar to many known cell envelope proteins.

                          10        20
                  ....*....|....*....|..
gi 1063722196  59 EMFRELDRNGDGQLDFWEVLTL 80
Cdd:cd00213    55 KIMKDLDVNKDGKVDFQEFLVL 76

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
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1063722196  31 DVNGDGRVSLQEYTDFLRQTAGLA----WIHPEMFR---ELDRNGDGQLDFWEVLT 79
Cdd:cd16224   171 DKDGDGFISLEEFLGDYRKDPTANedpeWIIVEKDRfvnDYDKDNDGKLDPQELLP 226

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 1063722196   27 FRAMDVNGDGRVSLQEYTDFLR 48
Cdd:smart00054   6 FRLFDKDGDGKIDFEEFKDLLK 27