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        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 320541949 346 KLRWTFSLYDINGDGFITREEMTDIVTAIYELMgrlpdecPEEEkikgkVEQIFQKMDTNRDGVVTLEEFLEA 418
Cdd:cd00051    1 ELREAFRLFDKDGDGTISADELKAALKSLGEGL-------SEEE-----IDEMIREVDKDGDGKIDFEEFLEL 61

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320541949 304 GANPT-LYAHYVFNTLDQDHSGIVSFEDFvqgLSILSR----GSVEEKLRWTFSLYDINGDGFITREEMTDIVTAIYElm 378
Cdd:PTZ00184  41 GQNPTeAELQDMINEVDADGNGTIDFPEF---LTLMARkmkdTDSEEEIKEAFKVFDRDGNGFISAAELRHVMTNLGE-- 115

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 320541949 379 gRLPDEcpeeekikgKVEQIFQKMDTNRDGVVTLEEF 415
Cdd:PTZ00184 116 -KLTDE---------EVDEMIREADVDGDGQINYEEF 142

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 320541949   346 KLRWTFSLYDINGDGFITREEMTDIVTAI 374
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

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        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 320541949 346 KLRWTFSLYDINGDGFITREEMTDIVTAIYELMgrlpdecPEEEkikgkVEQIFQKMDTNRDGVVTLEEFLEA 418
Cdd:cd00051    1 ELREAFRLFDKDGDGTISADELKAALKSLGEGL-------SEEE-----IDEMIREVDKDGDGKIDFEEFLEL 61

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 320541949 310 YAHYVFNTLDQDHSGIVSFEDFVQGLSILSRGSVEEKLRWTFSLYDINGDGFITREEMTDIVT 372
Cdd:cd00051    1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320541949 304 GANPT-LYAHYVFNTLDQDHSGIVSFEDFvqgLSILSR----GSVEEKLRWTFSLYDINGDGFITREEMTDIVTAIYElm 378
Cdd:PTZ00184  41 GQNPTeAELQDMINEVDADGNGTIDFPEF---LTLMARkmkdTDSEEEIKEAFKVFDRDGNGFISAAELRHVMTNLGE-- 115

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 320541949 379 gRLPDEcpeeekikgKVEQIFQKMDTNRDGVVTLEEF 415
Cdd:PTZ00184 116 -KLTDE---------EVDEMIREADVDGDGQINYEEF 142

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 320541949 310 YAHYVFNTLDQDHSGIVSFEDFVQGLSILSRGSVEEKLRWTFSLYDINGDGFITREEMtdiVTAIYELMGRlpdecPEee 389
Cdd:cd15898    1 WLRRQWIKADKDGDGKLSLKEIKKLLKRLNIRVSEKELKKLFKEVDTNGDGTLTFDEF---EELYKSLTER-----PE-- 70

                         90       100       110
                 ....*....|....*....|....*....|..
gi 320541949 390 kikgkVEQIFQKMDTNRDGVVTLEEFLEACRN 421
Cdd:cd15898   71 -----LEPIFKKYAGTNRDYMTLEEFIRFLRE 97

EF-hand motif found in phosphoinositide phospholipase C eta 1 (PI-PLC-eta1); PI-PLC-eta1, also termed 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-1, or phospholipase C-eta-1 (PLC-eta-1), or phospholipase C-like protein 3 (PLC-L3), 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 zona incerta and in the spinal cord. PI-PLC-eta1 may perform a fundamental role in the brain. It may also act in synergy with other PLC subtypes. For instance, it is activated via intracellular Ca2+ mobilization and then plays a role in the amplification of GPCR (G-protein-coupled receptor)-mediated PLC-beta signals. In addition, its activity can be stimulated by ionomycin. PI-PLC-eta1 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        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320541949 347 LRWTFSLYDINGDGFITREEmtdivtaIYELMGRLPDECPeeekiKGKVEQIFQKMDTNRD-GVVTLEEF 415
Cdd:cd16220    2 VKQTFEEADKNGDGLLNIEE-------IYQLMHKLNVNLP-----RRKVRQMFQEADTDENqGTLTFEEF 59

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320541949 315 FNTLDQDHSGIVSFEDFVQGLSILSRGSVEEKLRWTFSLYDINGDGFITREEMtdivTAIYELMGRLPDECPEEEkikgK 394
Cdd:NF041410  33 FAKLDSDGDGSVSQDELSSALSSKSDDGSLIDLSELFSDLDSDGDGSLSSDEL----AAAAPPPPPPPDQAPSTE----L 104

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 320541949 395 VEQIFQKMDTNRDGVVTLEEFLEACRNDDAISRSMSVFDT 434
Cdd:NF041410 105 ADDLLSALDTDGDGSISSDELSAGLTSAGSSADSSQLFSA 144

EF-hand motif found in phosphoinositide phospholipase C eta (PI-PLC-eta); PI-PLC-eta isozymes represent a class of neuron-specific metazoan PI-PLCs that are most abundant in the brain, particularly in the hippocampus, habenula, olfactory bulb, cerebellum, and throughout the cerebral cortex. They are phosphatidylinositol 4,5-bisphosphate-hydrolyzing enzymes that are more sensitive to Ca2+ than other PI-PLC isozymes. They function as calcium sensors activated by small increases in intracellular calcium concentrations. They are also activated through G-protein-coupled receptor (GPCR) stimulation, and further mediate GPCR signalling pathways. PI-PLC-eta isozymes contain 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. There are two PI-PLC-eta isozymes (1-2). Aside from the PI-PLC-eta isozymes identified in mammals, their eukaryotic homologs are also present in this family.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 320541949 347 LRWTFSLYDINGDGFITREEmtdivtaIYELMGRLPDECPeeekiKGKVEQIFQKMDT-NRDGVVTLEEFL 416
Cdd:cd16205    2 LKQTFEEADKNGDGLLSIGE-------ILQLMHKLNVNLP-----RRKVRQMFKEADTdDNQGTLDFEEFC 60

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 320541949  394 KVEQIFQKMDTNRDGVVTLEEFLEACR 420
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELLK 27

centrin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320541949 343 VEEKLRWTFSLYDINGDGFITREEMtdivtaiYELMGRLPDEcPEEEKIKgkveQIFQKMDTNRDGVVTLEEFLEACR-- 420
Cdd:PTZ00183  15 QKKEIREAFDLFDTDGSGTIDPKEL-------KVAMRSLGFE-PKKEEIK----QMIADVDKDGSGKIDFEEFLDIMTkk 82

                         90
                 ....*....|....*...
gi 320541949 421 -----NDDAISRSMSVFD 433
Cdd:PTZ00183  83 lgerdPREEILKAFRLFD 100

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 320541949 345 EKLRWtfSLYDINGDGFITREEMTDIVTaiyelmgrlPDECPEEEKIKgkVEQIFQKMDTNRDGVVTLEEFL 416
Cdd:cd16226  121 DERRW--KAADQDGDGKLTKEEFTAFLH---------PEEFPHMRDIV--VQETLEDIDKNKDGFISLEEYI 179

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 320541949   394 KVEQIFQKMDTNRDGVVTLEEFLEACRN 421
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKA 28

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 320541949 351 FSLYDINGDGFITREEMTDIvtaIYELMGRLPDECPEEEKIKGKVEQIFQKMDTNRDGVVTLEEF 415
Cdd:cd15902    5 WMHFDADGNGYIEGKELDSF---LRELLKALNGKDKTDDEVAEKKKEFMEKYDENEDGKIEIREL 66

Calgranulins: S-100 domain found in proteins belonging to the Calgranulin subgroup of the S100 family of EF-hand calcium-modulated proteins, including S100A8, S100A9, and S100A12 . Note that the S-100 hierarchy, to which this Calgranulin group belongs, contains only S-100 EF-hand domains, other EF-hands have been modeled separately. These proteins are expressed mainly in granulocytes, and are involved in inflammation, allergy, and neuritogenesis, as well as in host-parasite response. Calgranulins are modulated not only by calcium, but also by other metals such as zinc and copper. Structural data suggested that calgranulins may exist in multiple structural forms, homodimers, as well as hetero-oligomers. For example, the S100A8/S100A9 complex called calprotectin plays important roles in the regulation of inflammatory processes, wound repair, and regulating zinc-dependent enzymes as well as microbial growth.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 320541949 362 ITREEMTDIVTaiyelmgrlpDECP---EEEKIKGKVEQIFQKMDTNRDGVVTLEEFLE 417
Cdd:cd05030   27 LYKKEFKQLVE----------KELPnflKKEKNQKAIDKIFEDLDTNQDGQLSFEEFLV 75

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 320541949 355 DINGDGFITREEMTDIVTAIYELMgrlpDEcpEEEKIKgkveqiFQKMDTNRDGVVTLEEFL 416
Cdd:cd16227   46 DLNDDGFIDRKELKAWILRSFKML----DE--EEANER------FEEADEDGDGKVTWEEYL 95

EF-hand domain;

                          10        20
                  ....*....|....*....|....*....
gi 320541949  346 KLRWTFSLYDINGDGFITREEMTDIVTAI 374
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKALRSL 29

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 320541949 315 FNTLDQDHSGIVSFEDFVQ----------GLSILSRGSVEEKL----RWTFSLYDINGDGFITREEMTdivtAIYElmgr 380
Cdd:cd16227   78 FEEADEDGDGKVTWEEYLAdsfgyddednEEMIKDSTEDDLKLleddKEMFEAADLNKDGKLDKTEFS----AFQH---- 149

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 320541949 381 lPDECPEEEKIKgkVEQIFQKMDTNRDGVVTLEEFL 416
Cdd:cd16227  150 -PEEYPHMHPVL--IEQTLRDKDKDNDGFISFQEFL 182

EF-hand, calcium binding motif, found in calumenin; Calumenin, also termed crocalbin, or IEF SSP 9302, 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 is highly expressed in various brain regions. Thus it plays an important role in migration and differentiation of neurons, and/or in Ca2+ signaling between glial cells and neurons. Calumenin is involved in Ca2+ homeostasis through interacting with ryanodine receptor RyR2 and SERCA2. It acts as a novel regulator of SERCA2, and its expressional changes are tightly coupled with Ca2+-cycling of cardiomyocytes. Calumenin also forms a Ca2+-dependent complex with thrombospondin-1, which is broadly involved in haemostasis and thrombosis. Moreover, calumenin is a molecular chaperone that endogenously regulates the vitamin K-dependent gamma-carboxylation of several proteins, including blood coagulation factors (such as FII, FVII, FIX, FX, and proteins C, S and Z), cell survival factors (Gas6) and bone metabolism proteins (such as matrix Gla protein or MGP, osteocalcin and periostin), through targeting the gamma-glutamyl carboxylase. It also functions as a charged F508del-cystic fibrosis transmembrane regulator (CFTR) folding modulator, as well as a G551D-CFTR associated protein. Furthermore, the extracellular calumenin acts as a suppressor of cell migration and tumor metastasis. It binds to and stabilizes fibulin-1, and further inactivates extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320541949 318 LDQDHSGIVSFEDFVQGLSILSRGSVEEKLRWTFSLYDINGDGFITREEMTDiVTAIYELMGRLPDECPEEEKIKGKVEQ 397
Cdd:cd16228   44 IDEDKDGFVTEDELKAWIKFAQKRWIYEDVERQWKGHDLNEDGLVSWEEYKN-ATYGYILDDPDPDDGFNYKQMMVRDER 122

                         90
                 ....*....|....*...
gi 320541949 398 IFQKMDTNRDGVVTLEEF 415
Cdd:cd16228  123 RFKMADKDGDLRATKEEF 140

EF hand;

                          10        20
                  ....*....|....*....|.
gi 320541949  395 VEQIFQKMDTNRDGVVTLEEF 415
Cdd:pfam13202   1 LKDTFRQIDLNGDGKISKEEL 21

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 320541949 318 LDQDHSGIVSFEDFVQglSILSRGSVEEKLRW------TFSLY-DINGDGFITREEMTDIVtaiyelmgrLPDEC--PEE 388
Cdd:cd16226  165 IDKNKDGFISLEEYIG--DMYRDDDEEEDPDWvksereQFKEFrDKNKDGKMDREEVKDWI---------LPEDYdhAEA 233

                         90       100
                 ....*....|....*....|....*....
gi 320541949 389 EkikgkVEQIFQKMDTNRDGVVTLEEFLE 417
Cdd:cd16226  234 E-----AKHLIYEADDDKDGKLTKEEILD 257