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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1IKU_A       40 SGRITRQEFQTIYSkffpeadpkAYAQHVFRSFDANSDGTLDFKEYVIALHMTSAGKTNQKLEWAFSLYDVDGNGTISKN 119
Cdd:COG5126  19 DGVLERDDFEALFR---------RLWATLFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDLLDTDGDGKISAD 89

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*
1IKU_A      120 EVLEIVTAIfkmispedtkhlpedeNTPEKRAEKIWGFFGKKDDDKLTEKEFIEG 174
Cdd:COG5126  90 EFRRLLTAL----------------GVSEEEADELFARLDTDGDGKISFEEFVAA 128

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1IKU_A       40 SGRITRQEFQTIYSkffpeadpkAYAQHVFRSFDANSDGTLDFKEYVIALHMTSAGKTNQKLEWAFSLYDVDGNGTISKN 119
Cdd:COG5126  19 DGVLERDDFEALFR---------RLWATLFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDLLDTDGDGKISAD 89

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*
1IKU_A      120 EVLEIVTAIfkmispedtkhlpedeNTPEKRAEKIWGFFGKKDDDKLTEKEFIEG 174
Cdd:COG5126  90 EFRRLLTAL----------------GVSEEEADELFARLDTDGDGKISFEEFVAA 128

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
1IKU_A      100 KLEWAFSLYDVDGNGTISKNEVLEIVTAIfkmispedtkhlpeDENTPEKRAEKIWGFFGKKDDDKLTEKEFIEG 174
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKSL--------------GEGLSEEEIDEMIREVDKDGDGKIDFEEFLEL 61

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
                   ....*....|....*....|....*....
1IKU_A         100 KLEWAFSLYDVDGNGTISKNEVLEIVTAI 128
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1IKU_A        18 LNTKFTEEELSSWYQSF--LKECPSGRITRQEFQTIYsKFFPEADPKAYAQHVFRSFDANSDGTLDFKEYVI--ALHMTS 93
Cdd:PTZ00184   1 MADQLTEEQIAEFKEAFslFDKDGDGTITTKELGTVM-RSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTlmARKMKD 79

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
1IKU_A        94 aGKTNQKLEWAFSLYDVDGNGTISKNEVLEIVTAIFKMISPED 136
Cdd:PTZ00184  80 -TDSEEEIKEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEE 121

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1IKU_A       40 SGRITRQEFQTIYSkffpeadpkAYAQHVFRSFDANSDGTLDFKEYVIALHMTSAGKTNQKLEWAFSLYDVDGNGTISKN 119
Cdd:COG5126  19 DGVLERDDFEALFR---------RLWATLFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDLLDTDGDGKISAD 89

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*
1IKU_A      120 EVLEIVTAIfkmispedtkhlpedeNTPEKRAEKIWGFFGKKDDDKLTEKEFIEG 174
Cdd:COG5126  90 EFRRLLTAL----------------GVSEEEADELFARLDTDGDGKISFEEFVAA 128

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        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1IKU_A       26 ELSSWYQSFLKECpSGRITRQEFQTIYSK---FFPEADpkayAQHVFRSFDANSDGTLDFKEYViALHmtsagKTNQKLE 102
Cdd:cd16185   1 ELRQWFRAVDRDR-SGSIDVNELQKALAGgglLFSLAT----AEKLIRMFDRDGNGTIDFEEFA-ALH-----QFLSNMQ 69

                        90       100
                ....*....|....*....|.
1IKU_A      103 WAFSLYDVDGNGTISKNEVLE 123
Cdd:cd16185  70 NGFEQRDTSRSGRLDANEVHE 90

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1IKU_A       41 GRITRQEFqtiySKFF-PEADPKAYA---QHVFRSFDANSDGTLDFKEYV--IALHMTSAGKTNQKLEWAFsLYDVDGNG 114
Cdd:cd16227 137 GKLDKTEF----SAFQhPEEYPHMHPvliEQTLRDKDKDNDGFISFQEFLgdRAGHEDKEWLLVEKDRFDE-DYDKDGDG 211

                        90       100
                ....*....|....*....|....*.
1IKU_A      115 TISKNEVLEIVTAIFKMISPEDTKHL 140
Cdd:cd16227 212 KLDGEEILSWLVPDNEEIAEEEVDHL 237

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
                   ....*....|....*....|....*....
1IKU_A         100 KLEWAFSLYDVDGNGTISKNEVLEIVTAI 128
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1IKU_A        18 LNTKFTEEELSSWYQSF--LKECPSGRITRQEFQTIYsKFFPEADPKAYAQHVFRSFDANSDGTLDFKEYVI--ALHMTS 93
Cdd:PTZ00184   1 MADQLTEEQIAEFKEAFslFDKDGDGTITTKELGTVM-RSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTlmARKMKD 79

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
1IKU_A        94 aGKTNQKLEWAFSLYDVDGNGTISKNEVLEIVTAIFKMISPED 136
Cdd:PTZ00184  80 -TDSEEEIKEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEE 121

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1IKU_A       99 QKLEWAFSLYDVDGNGTISKNEVLEIVTAIFKM------------ISPED--TKHLPEDENTPEKRAEKIWGFFGKKDDD 164
Cdd:COG5126   5 RKLDRRFDLLDADGDGVLERDDFEALFRRLWATlfseadtdgdgrISREEfvAGMESLFEATVEPFARAAFDLLDTDGDG 84

                ....*..
1IKU_A      165 KLTEKEF 171
Cdd:COG5126  85 KISADEF 91

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1IKU_A       40 SGRITRQEFQTIYSKFFPEADPKA-------YAQHVFRSFDANSDGTLDFKEYVIAL------HMTSAGKTNQKL----- 101
Cdd:cd15902 104 SGFIEAKELKGFLKDLLLKNKKHVsppkldeYTKLILKEFDANKDGKLELDEMAKLLpvqenfLLKFQILGAMDLtkedf 183

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....
1IKU_A      102 EWAFSLYDVDGNGTISKNEVLEIVTAIFKMISPEDtkhlpeDENTPEKRAEKIWGFFGKKDDDKLTEKE 170
Cdd:cd15902 184 EKVFEHYDKDNNGVIEGNELDALLKDLLEKNKADI------DKPDLENFRDAILRACDKNKDGKIQKTE 246

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1IKU_A        4 KSGALSKEileELQL------NTKFTEEELSSWYQSFLKEcPSGRITRQEFQTIYsKFFpeadpkAYAQHVFRSFDANSD 77
Cdd:cd16180  13 RSGRISAK---ELQRalsngdWTPFSIETVRLMINMFDRD-RSGTINFDEFVGLW-KYI------QDWRRLFRRFDRDRS 81

                        90       100       110       120
                ....*....|....*....|....*....|....*....|
1IKU_A       78 GTLDFKEYVIALHMTSAGKTNQKLEWAFSLYDVDGNGTIS 117
Cdd:cd16180  82 GSIDFNELQNALSSFGYRLSPQFVQLLVRKFDRRRRGSIS 121

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
                ....*....|....*....|....*....|....*....|....*....
1IKU_A       72 FDANSDGTLDFKEYViALHmtsagKTNQKLEWAFSLYDVDGNGTISKNE 120
Cdd:cd16180  46 FDRDRSGTINFDEFV-GLW-----KYIQDWRRLFRRFDRDRSGSIDFNE 88

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

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*....
1IKU_A       36 KECPSGRITRQEFQTIYSKFFP-----EADPKAYAQhVFRSFDANSDGTLDFKEYVIAL 89
Cdd:cd00213  20 KEGDKDTLSKKELKELLETELPnflknQKDPEAVDK-IMKDLDVNKDGKVDFQEFLVLI 77

centrin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
1IKU_A        40 SGRITRQEFQTIYSKFFPEADPKAYAQHVFRSFDANSDGTLDFKEYVIALHMTSAGKTNQKLEWAFSLYDVDGNGTISKN 119
Cdd:PTZ00183  67 SGKIDFEEFLDIMTKKLGERDPREEILKAFRLFDDDKTGKISLKNLKRVAKELGETITDEELQEMIDEADRNGDGEISEE 146

                 ....*..
1IKU_A       120 EVLEIVT 126
Cdd:PTZ00183 147 EFYRIMK 153