EF-hand domain pair;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 218751877   50 EEKMKYCFEVFDLNGDGFISKEEMFHMLKNSLLKQPSEEDPdegikdlVEITLKKMDHDHDGKLSFADYELAVR 123
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRKLEEGEPLSDEE-------VEELFKEFDLDKDGRISFEEFLELYS 67

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 218751877  25 DKDNDGCVNVLEWIHGLSLFLRGS-LEEKMKYCFEVFDLNGDGFISKEEMFHMLKNsLLKQPSEEDPDEGIKDlveitlk 103
Cdd:PTZ00184  57 DADGNGTIDFPEFLTLMARKMKDTdSEEEIKEAFKVFDRDGNGFISAAELRHVMTN-LGEKLTDEEVDEMIRE------- 128

                         90
                 ....*....|....*
gi 218751877 104 kMDHDHDGKLSFADY 118
Cdd:PTZ00184 129 -ADVDGDGQINYEEF 142

EF-hand domain pair;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 218751877   50 EEKMKYCFEVFDLNGDGFISKEEMFHMLKNSLLKQPSEEDPdegikdlVEITLKKMDHDHDGKLSFADYELAVR 123
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRKLEEGEPLSDEE-------VEELFKEFDLDKDGRISFEEFLELYS 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        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 218751877  52 KMKYCFEVFDLNGDGFISKEEMFHMLKnSLLKQPSEEDPDEgikdlveiTLKKMDHDHDGKLSF 115
Cdd:cd00051    1 ELREAFRLFDKDGDGTISADELKAALK-SLGEGLSEEEIDE--------MIREVDKDGDGKIDF 55

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 218751877   18 KHLFRGFDKDNDGCVNVLEWIHGLSLFLRGS--LEEKMKYCFEVFDLNGDGFISKEEMFHMLK 78
Cdd:pfam13499   5 KEAFKLLDSDGDGYLDVEELKKLLRKLEEGEplSDEEVEELFKEFDLDKDGRISFEEFLELYS 67

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 218751877  13 LTKNCKHLFRGFDKDNDGCVNVLEWIHGLS------LFLRGSL---EEKMKyCFEVFDLNGDGFISKEEMFHMLKNsLLK 83
Cdd:cd16176   39 LSDQMKAFVDQYGQSTDGKIGIVELAQILPteenflLFFRQQLkssEEFMQ-TWRKYDADHSGFIEADELKSFLKD-LLK 116

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 218751877  84 QPSEEDPDEGIKDLVEITLKKMDHDHDGKLSFADYE--LAVREETLL 128
Cdd:cd16176  117 KANKPFDESKLEEYTHTMLKMFDSNNDGKLGLTEMArlLPVQENFLL 163

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 218751877  50 EEKMKYCFEVFDLNGDGFISKEEMFHMLKNSLLKQPSEEDPD-------------------EGIKDLVEITLKKMDHDHD 110
Cdd:COG5126    4 RRKLDRRFDLLDADGDGVLERDDFEALFRRLWATLFSEADTDgdgrisreefvagmeslfeATVEPFARAAFDLLDTDGD 83

                         90
                 ....*....|....
gi 218751877 111 GKLSFADYELAVRE 124
Cdd:COG5126   84 GKISADEFRRLLTA 97

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 218751877  60 FDLNGDGFISKEEMFHMLKNsLLKQPSEEDPDEGIKDLVEITLKKMDHDHDGKLSFADYE--LAVREETLLLEAFGPCLP 137
Cdd:cd16178  101 YDADSSGYISAAELKNFLRD-LFLQHKKVITEDKLDEYTDTMMKIFDKNKDGRLDLNDMAriLALQENFLLQFKMDAMSE 179

                 ....*
gi 218751877 138 DPKSQ 142
Cdd:cd16178  180 EERKR 184

EF-hand, calcium binding motif, found in Drosophila melanogaster calbindin-32 (CBN) and similar proteins; CBN, the product of the cbn gene, is a Drosophila homolog to vertebrate neuronal six EF-hand calcium binding proteins. It is expressed through most of ontogenesis with a selective distribution in the nervous system and in a few small adult thoracic muscles. Its precise biological role remains unclear. CBN contains six EF-hand motifs, but some of them may not bind calcium ions due to the lack of key residues.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 218751877  57 FEVFDLNGDGFISKEEMFHMLKNsLLKQPSEEDPDEGIKDLVEITLKKMDHDHDGKLS 114
Cdd:cd16179  194 FALYDRDNNGTIENEELTGFLKD-LLELVQEDYDEQDLEEFKEIILRGWDFNNDGKIS 250

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 218751877  48 SLEEKMKYcFEVFDLNGDGFISKEEmFHMLKNSllkqpsEEDPDEgIKDLVEITLKKMDHDHDGKLSFADY 118
Cdd:cd16227  120 LLEDDKEM-FEAADLNKDGKLDKTE-FSAFQHP------EEYPHM-HPVLIEQTLRDKDKDNDGFISFQEF 181

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 218751877  20 LFRGFDKDNDGCVNVLE---WIHGLSL-FLRGSLEEKMKycfeVFDLNGDGFISKEEMFHMLKNSLLKQPSEEDPDEGIK 95
Cdd:cd16226   40 IVDKIDKNGDGFVTEEElkdWIKYVQKkYIREDVDRQWK----EYDPNKDGKLSWEEYKKATYGFLDDEEEDDDLHESYK 115

                         90       100
                 ....*....|....*....|..
gi 218751877  96 DLVEITLKKM---DHDHDGKLS 114
Cdd:cd16226  116 KMIRRDERRWkaaDQDGDGKLT 137