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.

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42569601 268 DHARFeLMSEVHKHLKRFSPkhlikdgELSKESLKSLFKKTDKNKDGKIQISELKDLtIElsnFGRMRYDINELAKAFlE 347
Cdd:cd16226  12 DHEAF-LGKEEAKEFDQLTP-------EESKERLGIIVDKIDKNGDGFVTEEELKDW-IK---YVQKKYIREDVDRQW-K 78

                ....*...
gi 42569601 348 DFDGDNDG 355
Cdd:cd16226  79 EYDPNKDG 86

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.

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42569601 268 DHARFeLMSEVHKHLKRFSPkhlikdgELSKESLKSLFKKTDKNKDGKIQISELKDLtIElsnFGRMRYDINELAKAFlE 347
Cdd:cd16226  12 DHEAF-LGKEEAKEFDQLTP-------EESKERLGIIVDKIDKNGDGFVTEEELKDW-IK---YVQKKYIREDVDRQW-K 78

                ....*...
gi 42569601 348 DFDGDNDG 355
Cdd:cd16226  79 EYDPNKDG 86

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.

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42569601 268 DHARFeLMSEVHKHLKRFSPkhlikdgELSKESLKSLFKKTDKNKDGKIQISELKDLtIElsnFGRMRYDINELAKAFlE 347
Cdd:cd16226  12 DHEAF-LGKEEAKEFDQLTP-------EESKERLGIIVDKIDKNGDGFVTEEELKDW-IK---YVQKKYIREDVDRQW-K 78

                ....*...
gi 42569601 348 DFDGDNDG 355
Cdd:cd16226  79 EYDPNKDG 86

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).

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                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 42569601 295 ELSKESLKSLFKKTDKNKDGKIQISELKDLtIELSnfgrMRYDINELAKAFLEDFDGDNDG 355
Cdd:cd16227  32 EEAKRRLAVLAKKMDLNDDGFIDRKELKAW-ILRS----FKMLDEEEANERFEEADEDGDG 87

EF-hand, extracellular calcium-binding (EC) motif, found in testicans; Testicans are nervous system-expressed proteoglycans that play important roles in the regulation of protease activity, as well as in the determination of age at menarche. Testican-1 (TICN1, also termed protein SPOCK) is a secreted chimeric proteoglycan that is highly expressed in brain and carries both chondroitin and heparan sulfate glycosaminoglycan side chains. It has been implicated in autoimmune disease. It also acts as a regulator of bone morphogenetic protein (BMP) signaling and show critical functions in the nervous system. Testican-2 (TICN2, also termed protein SPOCK2) is an extracellular heparan sulphate proteoglycan highly expressed in brain. It may play regulatory roles in the development of the central nervous system. It also participates in diverse steps of neurogenesis. TICN1, but not TICN2, inhibits cathepsin L. TICN1 also inhibits attachment and neurite outgrowth in cultures of N2A neuroblastoma cells, While TICN2 is able to inhibit neurite outgrowth from primary cerebellar cells. Testicans contain an N-terminal signal peptide, a testican-specific domain followed by a follistatin-like (FS) domain, an extracellular calcium-binding (EC) domain including a pair of EF hands, a thyroglobulin-like domain (TY), and a C-terminal region with two putative glycosaminoglycan attachment sites. The substitution of a ligating Asp residue by Tyr orTyr in the +Y position of EF hand 2 in testican-2 could prevent Ca2+ binding to this site and also cause EF-hand 1 to bind one Ca2+ with low affinity. The substitution of a ligating Asp residue by Phe or Tyr in the +Y position of EF-hand 2 in testicans could prevent Ca2+ binding to this site and also cause EF-hand 1 to bind one Ca2+ ion with low affinity.

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42569601 272 FELMSEVHKHLK------RFSPKHLIKdgelSKESLKSLFKKTDKNKDGKIQISELKDltielsnfgrMRYDINELA-KA 344
Cdd:cd16232  17 FSVLHEQSNKAKktssskRFDKSHLPE----CKPSVGWMFNQLDTNNDLHLSQSELYD----------LELDKYEPCiKP 82

                        90
                ....*....|.
gi 42569601 345 FLEDFDGDNDG 355
Cdd:cd16232  83 FLDSCDRNKDG 93