calmodulin; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1198817754   9 AEQLTDEQKNEFRAAFDIFVQDAeDGCISTKELGKVMRMLGQNPTPEELQEMIDEVDEDGSGTVDFEEFLVMMVRCMKDD 88
Cdd:PTZ00184    2 ADQLTEEQIAEFKEAFSLFDKDG-DGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLMARKMKDT 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1198817754  89 SKgrpEEELAELFRMFDKNADGYIDLDELKLMLEATGEAITEDDIEELMRDGDKNNDGKIDYDEFLEFM 157
Cdd:PTZ00184   81 DS---EEEIKEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEFVKMM 146

calmodulin; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1198817754   9 AEQLTDEQKNEFRAAFDIFVQDAeDGCISTKELGKVMRMLGQNPTPEELQEMIDEVDEDGSGTVDFEEFLVMMVRCMKDD 88
Cdd:PTZ00184    2 ADQLTEEQIAEFKEAFSLFDKDG-DGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLMARKMKDT 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1198817754  89 SKgrpEEELAELFRMFDKNADGYIDLDELKLMLEATGEAITEDDIEELMRDGDKNNDGKIDYDEFLEFM 157
Cdd:PTZ00184   81 DS---EEEIKEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEFVKMM 146

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 1198817754  96 ELAELFRMFDKNADGYIDLDELKLMLEATGEAITEDDIEELMRDGDKNNDGKIDYDEFLEFMK 158
Cdd:cd00051     1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

XopAW family type III secretion system calcium-binding effector;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1198817754  33 DGCISTKELGKvmrMLGQNP---TPEELQEMIDEVDEDGSGTVDFEEFLVMMvRCMKDDSKGRPEEELAE-LFRMFDKNA 108
Cdd:NF041410   41 DGSVSQDELSS---ALSSKSddgSLIDLSELFSDLDSDGDGSLSSDELAAAA-PPPPPPPDQAPSTELADdLLSALDTDG 116

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1198817754 109 DGYIDLDELKLMLEATGeaiTEDDIEELMRDGDKNNDGKIDYDEF 153
Cdd:NF041410  117 DGSISSDELSAGLTSAG---SSADSSQLFSALDSDGDGSVSSDEL 158

XopAW family type III secretion system calcium-binding effector;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1198817754  89 SKGRPEEELAELFRMFDKNADGYIDLDELKLMLEATGEAITEDDIEELMRDGDKNNDGKIDYDEFLEFMK 158
Cdd:NF041410   21 SSARSQQFQKQLFAKLDSDGDGSVSQDELSSALSSKSDDGSLIDLSELFSDLDSDGDGSLSSDELAAAAP 90

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 1198817754   56 ELQEMIDEVDEDGSGTVDFEEFLVMM 81
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLL 26

calmodulin; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1198817754   9 AEQLTDEQKNEFRAAFDIFVQDAeDGCISTKELGKVMRMLGQNPTPEELQEMIDEVDEDGSGTVDFEEFLVMMVRCMKDD 88
Cdd:PTZ00184    2 ADQLTEEQIAEFKEAFSLFDKDG-DGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLMARKMKDT 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1198817754  89 SKgrpEEELAELFRMFDKNADGYIDLDELKLMLEATGEAITEDDIEELMRDGDKNNDGKIDYDEFLEFM 157
Cdd:PTZ00184   81 DS---EEEIKEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEFVKMM 146

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1198817754  14 DEQKNEFRAAFDIFVQDAeDGCISTKELGKVMRMLgqnptpeeLQEMIDEVDEDGSGTVDFEEFLVMMVRCMKDDSkgrp 93
Cdd:COG5126     1 DLQRRKLDRRFDLLDADG-DGVLERDDFEALFRRL--------WATLFSEADTDGDGRISREEFVAGMESLFEATV---- 67

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1198817754  94 EEELAELFRMFDKNADGYIDLDELKLMLEATGeaITEDDIEELMRDGDKNNDGKIDYDEFLEFMKG 159
Cdd:COG5126    68 EPFARAAFDLLDTDGDGKISADEFRRLLTALG--VSEEEADELFARLDTDGDGKISFEEFVAAVRD 131

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 1198817754  19 EFRAAFDIFVQDaEDGCISTKELGKVMRMLGQNPTPEELQEMIDEVDEDGSGTVDFEEFLVMM 81
Cdd:cd00051     1 ELREAFRLFDKD-GDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELM 62

Penta-EF hand, calcium binding motifs, found in Group I PEF proteins; The family corresponds to Group I PEF proteins that have been found not only in higher animals but also in lower animals, plants, fungi and protists. Group I PEF proteins include apoptosis-linked gene 2 protein (ALG-2), peflin and similar proteins. ALG-2, also termed programmed cell death protein 6 (PDCD6), is a widely expressed calcium-binding modulator protein associated with cell proliferation and death, as well as cell survival. It forms a homodimer in the cell or a heterodimer with its closest paralog peflin. Among the PEF proteins, ALG-2 can bind three Ca2+ ions through its EF1, EF3, and EF5 hands, where it is unique in that its EF5 hand binds Ca2+ ion in a canonical coordination. Peflin 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+.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1198817754  34 GCISTKELGKVMRMLGQNP-TPEELQEMIDEVDEDGSGTVDFEEF--LVMMVRCMKddskgrpeeelaELFRMFDKNADG 110
Cdd:cd16180    15 GRISAKELQRALSNGDWTPfSIETVRLMINMFDRDRSGTINFDEFvgLWKYIQDWR------------RLFRRFDRDRSG 82

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1198817754 111 YIDLDELKLMLEATGEAITEDDIEELMRDGDKNNDGKIDYDEFLE 155
Cdd:cd16180    83 SIDFNELQNALSSFGYRLSPQFVQLLVRKFDRRRRGSISFDDFVE 127

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1198817754  55 EELQEMIDEVDEDGSGTVDFEEFLVMMVRcmkddskgrpeeELAELFRMFDKNADGYIDLDELKLMLEATGEAITEDDIE 134
Cdd:COG5126     5 RKLDRRFDLLDADGDGVLERDDFEALFRR------------LWATLFSEADTDGDGRISREEFVAGMESLFEATVEPFAR 72

                          90       100
                  ....*....|....*....|....*..
gi 1198817754 135 ELMRDGDKNNDGKIDYDEFLEFMKGVE 161
Cdd:COG5126    73 AAFDLLDTDGDGKISADEFRRLLTALG 99

EF-hand, calcium binding motif, found in alpha-parvalbumin; Alpha-parvalbumin is cytosolic Ca2+/Mg2+-binding protein expressed mainly in fast-twitch skeletal myofibrils, where it may act as a soluble relaxing factor facilitating the Ca2+-mediated relaxation phase. It is also expressed in rapidly firing neurons, particularly GABA-ergic neurons, and thus may confer protection against Ca2+ toxicity. The major role of alpha-parvalbumin is metal buffering and transport of Ca2+. It binds different metal cations, and exhibits very high affinity for Ca2+ and physiologically significant affinity for Mg2+. Alpha-parvalbumin is characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. Both metal ion-binding sites in alpha-parvalbumin are high-affinity sites. Additionally, in contrast to beta-parvalbumin, alpha-parvalbumin is less acidic and has an additional residue in the C-terminal helix.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1198817754  90 KGRPEEELAELFRMFDKNADGYIDLDELKLMLE---ATGEAITEDDIEELMRDGDKNNDGKIDYDEF 153
Cdd:cd16254    29 KKKSADDVKKVFHILDKDKSGFIEEDELKFVLKgfsPDGRDLSDKETKALLAAGDKDGDGKIGIDEF 95

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 1198817754  56 ELQEMIDEVDEDGSGTVDFEEFLvmmvRCMKDDSKGRPEEELAELFRMFDKNADGYIDLDELKLML 121
Cdd:cd00051     1 ELREAFRLFDKDGDGTISADELK----AALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELM 62

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 1198817754  30 DAEDGCISTKELGKVMRMLGQNP-----TPEELQEMIDEVDEDGSGTVDFEEF--LVMMVRCMKddskgrpeeelaELFR 102
Cdd:cd15897    10 AGDDGEISATELQQALSNVGWTHfdlgfSLETCRSMIAMMDRDHSGKLNFSEFkgLWNYIKAWQ------------EIFR 77

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1198817754 103 MFDKNADGYIDLDELKLMLEATGEAITEDDIEELMRDGDKNNdGKIDYDEFLE 155
Cdd:cd15897    78 TYDTDGSGTIDSNELRQALSGAGYRLSEQTYDIIIRRYDRGR-GNIDFDDFIQ 129

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 1198817754  57 LQEMIDEVDEDGSGTVDFEEFLVMMVRcmkdDSKGRPEEELAELFRMFDKNADGYIDLDELKLMLeatGEAITEDDIEEL 136
Cdd:cd15898     2 LRRQWIKADKDGDGKLSLKEIKKLLKR----LNIRVSEKELKKLFKEVDTNGDGTLTFDEFEELY---KSLTERPELEPI 74

                          90       100
                  ....*....|....*....|....
gi 1198817754 137 MRDGDKNNDGKIDYDEFLEFMKGV 160
Cdd:cd15898    75 FKKYAGTNRDYMTLEEFIRFLREE 98

Penta-EF hand, calcium binding motifs, found in PEF calpain family; The PEF calpain family belongs to the second group of penta-EF hand (PEF) proteins. It includes classical (also called conventional or typical) calpain (referring to a calcium-dependent papain-like enzymes, EC 3.4.22.17) large catalytic subunits (CAPN1, 2, 3, 8, 9, 11, 12, 13, 14) and two calpain small subunits (CAPNS1 and CAPNS2), which are largely confined to animals (metazoans). These PEF-containing are nonlysosomal intracellular calcium-activated intracellular cysteine proteases that play important roles in the degradation or functional modulation in a variety of substrates in response to calcium signalling. The classical mu- and m-calpains are heterodimers consisting of homologous but a distinct (large) L-subunit/chain (CAPN1 or CAPN2) and a common (small) S-subunit/chain (CAPNS1 or CAPNS2). These L-subunits (CAPN1 and CAPN2) and S-subunit CAPNS1 are ubiquitously found in all tissues. Other calpains likely consist of an isolated L-subunit/chain alone. Many of them, such as CAPNS2, CAPN3 (in skeletal muscle, or lens), CAPN8 (in stomach), CAPN9 (in digestive tracts), CAPN11 (in testis), CAPN12 (in follicles), are tissue-specific and have specific functions in distinct organs. The L-subunits of similar structure (called CALPA and B) also have been found in Drosophila melanogaster. The S-subunit seems to have a chaperone-like function for proper folding of the L-subunit. The catalytic L-subunits contain a short N-terminal anchor helix, followed by a calpain cysteine protease (CysPc) domain, a C2-domain-like (C2L) domain, and a C-terminal Ca2+-binding penta-EF-hand (PEF) domain. The S-subunits only have the PEF domain following an N-terminal Gly-rich hydrophobic domain. The calpains undergo a rearrangement of the protein backbone upon Ca2+-binding.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1198817754  32 EDGCISTKELGKVM------RMLGQNPTPEEL-QEMIDEVDEDGSGTVDFEEFLVMMVRCmkddskgrpeEELAELFRMF 104
Cdd:cd16182    12 EDEEIDAVELQKLLnasllkDMPKFDGFSLETcRSLIALMDTNGSGRLDLEEFKTLWSDL----------KKWQAIFKKF 81

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1198817754 105 DKNADGYIDLDELKLMLEATGEAITEDDIEELM-RDGDKNndGKIDYDEFLEFM 157
Cdd:cd16182    82 DTDRSGTLSSYELRKALESAGFHLSNKVLQALVlRYADST--GRITFEDFVSCL 133

XopAW family type III secretion system calcium-binding effector;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1198817754  89 SKGRPEEELAELFRMFDKNADGYIDLDELKLMLEATGEAITEDDIEELMRDGDKNNDGKIDYDEFLEFMK 158
Cdd:NF041410   21 SSARSQQFQKQLFAKLDSDGDGSVSQDELSSALSSKSDDGSLIDLSELFSDLDSDGDGSLSSDELAAAAP 90

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 1198817754  95 EELAELFRMFDKNADGYIDLDELKLMLEATGEAITEDDIEELMRDGDKNNDGKIDYDEFLEFMKGVE 161
Cdd:cd16226    35 ERLGIIVDKIDKNGDGFVTEEELKDWIKYVQKKYIREDVDRQWKEYDPNKDGKLSWEEYKKATYGFL 101

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1198817754  96 ELAELFRMFDKNADGYIDLDELKLMLEATGEAITEDDIEELMRDGDKNNDGKIDYDEFLEF 156
Cdd:cd16185     1 ELRQWFRAVDRDRSGSIDVNELQKALAGGGLLFSLATAEKLIRMFDRDGNGTIDFEEFAAL 61

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 1198817754  32 EDGCISTKELGKVMRMLGQNPTPEELQEMIDEVDEDGSGTVDFEEFLV----MMVRCMKDDSKGRPEEEL------AELF 101
Cdd:cd16227    49 DDGFIDRKELKAWILRSFKMLDEEEANERFEEADEDGDGKVTWEEYLAdsfgYDDEDNEEMIKDSTEDDLklleddKEMF 128

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1198817754 102 RMFDKNADGYIDLDELKLMLEATG-EAITEDDIEELMRDGDKNNDGKIDYDEFL 154
Cdd:cd16227   129 EAADLNKDGKLDKTEFSAFQHPEEyPHMHPVLIEQTLRDKDKDNDGFISFQEFL 182

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 1198817754  54 PEELQEMIDEVDEDGSGTVDFEEFLVMMVrcmKDDSKGRPEEELAELFRMFDKNADGYIDLDELKLMLEATGEAITEDDI 133
Cdd:cd16227   158 PVLIEQTLRDKDKDNDGFISFQEFLGDRA---GHEDKEWLLVEKDRFDEDYDKDGDGKLDGEEILSWLVPDNEEIAEEEV 234

                          90       100
                  ....*....|....*....|..
gi 1198817754 134 EELMRDGDKNNDGKIDYDEFLE 155
Cdd:cd16227   235 DHLFASADDDHDDRLSFDEILD 256

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1198817754  55 EELQEMIDEVDEDGSGTVDFEEFLVMMVRCMKDDSKgrPEEELAELFRMFDKNADGYIDLDELK 118
Cdd:pfam13499   2 EKLKEAFKLLDSDGDGYLDVEELKKLLRKLEEGEPL--SDEEVEELFKEFDLDKDGRISFEEFL 63

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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1198817754  57 LQEMIDEVDEDGSGTVDFEEFLVMMVRcmKDDSKGRPEEELAELFRM---FDKNADGYIDLDELKLMLEATGEAITEDDI 133
Cdd:cd16224   163 IQEALEEHDKDGDGFISLEEFLGDYRK--DPTANEDPEWIIVEKDRFvndYDKDNDGKLDPQELLPWVVPNNYGIAQEEA 240

                          90       100
                  ....*....|....*....|..
gi 1198817754 134 EELMRDGDKNNDGKIDYDEFLE 155
Cdd:cd16224   241 LHLIDEMDLNGDGRLSEEEILE 262

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 1198817754  58 QEMIDEVDEDGSGTVDFEEFLVMMVRC---MKDDSKGRPEEELAELFRmfDKNADGYIDLDELKLMLEATGEAITEDDIE 134
Cdd:cd16226   159 QETLEDIDKNKDGFISLEEYIGDMYRDddeEEDPDWVKSEREQFKEFR--DKNKDGKMDREEVKDWILPEDYDHAEAEAK 236

                          90       100
                  ....*....|....*....|.
gi 1198817754 135 ELMRDGDKNNDGKIDYDEFLE 155
Cdd:cd16226   237 HLIYEADDDKDGKLTKEEILD 257

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 1198817754  57 LQEMIDEVDEDGSGTVDFEEFLVMMVRCMKDDSKGRPEEELAELFR-MFDKNADGYIDLDELKLMLEATGEAITEDDIEE 135
Cdd:cd15899   162 IKETLEDLDKNGDGFISLEEFISDPYSADENEEEPEWVKVEKERFVeLRDKDKDGKLDGEELLSWVDPSNQEIALEEAKH 241

                          90       100
                  ....*....|....*....|
gi 1198817754 136 LMRDGDKNNDGKIDYDEFLE 155
Cdd:cd15899   242 LIAESDENKDGKLSPEEILD 261

Penta-EF hand, calcium binding motifs, found in Drosophila melanogaster calpain-A (CalpA), calpain-B (CalpB), and similar proteins; The family contains two calpains that have been found in Drosophila, CalpA and CalpB. CalpA, also termed calcium-activated neutral proteinase A (CANP A), or calpain-A catalytic subunit, is a Drosophila calpain homolog specifically expressed in a few neurons in the central nervous system, in scattered endocrine cells in the midgut, and in blood cells. CalpB, also termed calcium-activated neutral proteinase B (CANP B), contains calpain-B catalytic subunit 1 and calpain-B catalytic subunit 2. Both CalpA and CalpB are closely related to that of vertebrate calpains, and they share similar domain architecture, which consists of four domains: the N-terminal domain I, the catalytic domain II carrying the three active site residues, Cys, His and Asn, the Ca2+-regulated phospholipid-binding domain III, and penta-EF-hand Ca2+-binding domain IV. Besides, CalpA and CalpB display some distinguishing structural features that are not found in mammalian typical calpains. CalpA harbors a 76 amino acid long hydrophobic stretch inserted in domain IV, which may be involved in membrane attachment of this enzyme. CalpB has an unusually long N-terminal tail of 224 amino acids, which belongs to the class of intrinsically unstructured proteins (IUP) and may become ordered upon binding to target protein(s). Moreover, they do not need small regulatory subunits for their catalytic activity, and their proteolytic function is not regulated by an intrinsic inhibitor as the Drosophila genome contains neither regulatory subunit nor calpastatin orthologs. As a result, they may exist as a monomer or perhaps as a homo- or heterodimer together with a second large subunit. Furthermore, both CalpA and CalpB are dispensable for viability and fertility and do not share vital functions during Drosophila development. Phosphatidylinositol 4,5-diphosphate, phosphatidylinositol 4-monophosphate, phosphatidylinositol, and phosphatidic acid can stimulate the activity and the rate of activation of CalpA, but not CalpB. Calpain A modulates Toll responses by limited Cactus/IkappaB proteolysis. CalpB directly interacts with talin, an important component of the focal adhesion complex, and functions as an important modulator in border cell migration within egg chambers, which may act via the digestion of talin. CalpB can be phosphorylated by cAMP-dependent protein kinase (protein kinase A, PKA; EC 2.7.11.11) at Ser240 and Ser845, as well as by mitogen-activated protein kinase (ERK1 and ERK2; EC 2.7.11.24) at Thr747. The activation of the ERK pathway by extracellular signals results in the phosphorylation and activation of calpain B. In Schneider cells (S2), calpain B was mainly in the cytoplasm and upon a rise in Ca2+ the enzyme adhered to intracellular membranes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1198817754  60 MIDEVDEDGSGTVDFEEF--LVMMVRCMKDdskgrpeeelaeLFRMFDKNADGYIDLDELKLMLEATGEAITEDDIEEL- 136
Cdd:cd16196    46 MVAMMDVDRSGKLGFEEFkkLWEDLRSWKR------------VFKLFDTDGSGSFSSFELRNALNSAGFRLSNATLNALv 113

                          90       100
                  ....*....|....*....|.
gi 1198817754 137 MRDGDKnnDGKIDYDEFLEFM 157
Cdd:cd16196   114 LRYSNK--DGRISFDDFIMCA 132

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 1198817754  53 TPEE----LQEMIDEVDEDGSGTVDFEEflvmMVRCMKDDSKGRPEEELAELFRMFDKNADGYIDLDELKLMLEATGEAI 128
Cdd:cd16226    29 TPEEskerLGIIVDKIDKNGDGFVTEEE----LKDWIKYVQKKYIREDVDRQWKEYDPNKDGKLSWEEYKKATYGFLDDE 104

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 1198817754 129 TEDDI------EELMRDG------DKNNDGKIDYDEFLEFM 157
Cdd:cd16226   105 EEDDDlhesykKMIRRDErrwkaaDQDGDGKLTKEEFTAFL 145

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 1198817754  33 DGCISTKELGKVMRMLGQNPTPEELQEMIDEVDEDGSGTVDFEEFLVMMVRCMKDDSK-----GRPEEELAEL------- 100
Cdd:cd15899    49 DGFISAKELHSWILESFKRHAMEESKEQFRAVDPDEDGHVSWDEYKNDTYGSVGDDEEnvadnIKEDEEYKKLllkdkkr 128

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1198817754 101 FRMFDKNADGYIDLDELkLMLEATGEA--ITEDDIEELMRDGDKNNDGKIDYDEFLEFMKG 159
Cdd:cd15899   129 FEAADQDGDLILTLEEF-LAFLHPEESpyMLDFVIKETLEDLDKNGDGFISLEEFISDPYS 188

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 1198817754  15 EQKNEFRAAFDifvqDAEDGCISTKELGKVMRMLGQN------PTPEELQEMIDEV----DEDGSGTVDFEEFLVMMVRC 84
Cdd:cd15902    44 EKKKEFMEKYD----ENEDGKIEIRELANILPTEENFlllfrrEQPLISSVEFMKIwrkyDTDGSGFIEAKELKGFLKDL 119

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1198817754  85 MKDDSKGRPEEELAE----LFRMFDKNADGYIDLDELKLML-----------EATGEAITEDDIEELMRDGDKNNDGKID 149
Cdd:cd15902   120 LLKNKKHVSPPKLDEytklILKEFDANKDGKLELDEMAKLLpvqenfllkfqILGAMDLTKEDFEKVFEHYDKDNNGVIE 199

                  ....*....
gi 1198817754 150 YDEFLEFMK 158
Cdd:cd15902   200 GNELDALLK 208

EF-hand domain;

                          10        20        30
                  ....*....|....*....|....*....|
gi 1198817754  96 ELAELFRMFDKNADGYIDLDELKLMLEATG 125
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKALRSLG 30

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 1198817754  93 PEEE----LAELFRMFDKNADGYIDLDELKLMLEATGEAITEDDIEELMRDGDKNNDGKIDYDEFL 154
Cdd:cd16227    30 PPEEakrrLAVLAKKMDLNDDGFIDRKELKAWILRSFKMLDEEEANERFEEADEDGDGKVTWEEYL 95

Penta-EF hand, calcium binding motifs, found in sorcin, grancalcin, and similar proteins; The family corresponds to the second group of penta-EF hand (PEF) proteins that includes sorcin, grancalcin, and similar proteins. Sorcin, also termed 22 kDa Ca2+-binding protein, CP-22, or V19, is a soluble resistance-related calcium-binding protein that is expressed in normal mammalian tissues, such as the liver, lungs and heart. It contains a flexible glycine and proline-rich N-terminal extension and five EF-hand motifs that associate with membranes in a calcium-dependent manner. It may harbor three potential Ca2+ binding sites through its EF1, EF2 and EF3 hands. However, binding of only two Ca2+/monomer suffices to trigger the conformational change that exposes hydrophobic regions and leads to interaction with the respective targets. Sorcin forms homodimers through the association of the unpaired EF5 hand. Among the PEF proteins, sorcin is unique in that it contains potential phosphorylation sites by cAMP-dependent protein kinase (PKA), and it can form a tetramer at slightly acid pH values although remaining a stable dimer at neutral pH. Grancalcin (GCA) is a cytosolic Ca2+-binding protein specifically expressed in neutrophils and monocytes/macrophages. It can strongly interact with sorcin to form a heterodimer and further modulate the function of sorcin. GCA exists as homodimers in solution. It contains five EF-hand motifs attached to an N-terminal region of an approximately 50 residue-long segment rich in glycines and prolines. In contrast with sorcin, GCA binds two Ca2+ ions through its EF1 and EF3 hands.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1198817754  33 DGCISTKELGKVMRMLGQNPTP-----EELQEMIDEVDEDGSGTVDFEEFLVMMvRCMkddskgrpeEELAELFRMFDKN 107
Cdd:cd16181    13 DGQIDADELQRCLTQSGISGNYqpfslETCRLMIAMLDRDHSGKMGFNEFKELW-AAL---------NQWKTTFMQYDRD 82

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1198817754 108 ADGYIDLDELKLMLEATGEAITEDDIEELMRDGDKNndGKIDYDEFL 154
Cdd:cd16181    83 RSGTVEPQELQQAIRSFGYNLSPQALNVIVKRYSKN--GRITFDDFV 127

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 1198817754  58 QEMIDEVDEDGSGTVDFEEFLVMMVRCMKDDSKGRPEEELAELFRMF----DKNADGYIDLDELKLMLEATGEAITEDDI 133
Cdd:cd16225   171 KEILHDLDQDGDEKLTLDEFVSLPPGTVEEQQAEDDDEWKKERKKEFeeviDLNHDGKVTKEELEEYMDPRNERHALNEA 250

                          90       100
                  ....*....|....*....|..
gi 1198817754 134 EELMRDGDKNNDGKIDYDEFLE 155
Cdd:cd16225   251 KQLIAVADENKDGKLSLEEILK 272