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 1622854142  65 AEHVFRTFDTNGDGTIDFREFIIALSVTSRGKLEQKLKWAFSMYDLDGNGYISRSEMLEIVQ 126
Cdd:cd00051     2 LREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

calmodulin; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622854142  73 DTNGDGTIDFREFIIALSVTSR-GKLEQKLKWAFSMYDLDGNGYISRSEMLEIvqaiykMVSSVMKMPEDEstpekrTDK 151
Cdd:PTZ00184   57 DADGNGTIDFPEFLTLMARKMKdTDSEEEIKEAFKVFDRDGNGFISAAELRHV------MTNLGEKLTDEE------VDE 124

                          90       100
                  ....*....|....*....|
gi 1622854142 152 IFRQMDTNNDGKLSLEEFIK 171
Cdd:PTZ00184  125 MIREADVDGDGQINYEEFVK 144

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 1622854142  100 KLKWAFSMYDLDGNGYISRSEMLEIVQAI 128
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
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1622854142  65 AEHVFRTFDTNGDGTIDFREFIIALSVTSRGKLEQKLKWAFSMYDLDGNGYISRSEMLEIVQ 126
Cdd:cd00051     2 LREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

XopAW family type III secretion system calcium-binding effector;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622854142  63 KFAEHVFRTFDTNGDGTIDFREFIIALSVTSRGKLEQKLKWAFSMYDLDGNGYISRSEMleivqaiykmvSSVMKMP--- 139
Cdd:NF041410   27 QFQKQLFAKLDSDGDGSVSQDELSSALSSKSDDGSLIDLSELFSDLDSDGDGSLSSDEL-----------AAAAPPPppp 95

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 1622854142 140 EDESTPEKRTDKIFRQMDTNNDGKLSLEEFIKGAKSDPS 178
Cdd:NF041410   96 PDQAPSTELADDLLSALDTDGDGSISSDELSAGLTSAGS 134

EF-hand domain pair;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1622854142  98 EQKLKWAFSMYDLDGNGYISRSEMLEIVQAIYkmvssvmkmpEDESTPEKRTDKIFRQMDTNNDGKLSLEEFIKGAK 174
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRKLE----------EGEPLSDEEVEELFKEFDLDKDGRISFEEFLELYS 67

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 1622854142  41 GHLTVDEFKKIYAnffPYGDASKFA---EHVFRTFDTNGDGTIDFREFI--IALSVTSRGKLEQKLKWAFSmYDLDGNGY 115
Cdd:cd16227   137 GKLDKTEFSAFQH---PEEYPHMHPvliEQTLRDKDKDNDGFISFQEFLgdRAGHEDKEWLLVEKDRFDED-YDKDGDGK 212

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1622854142 116 ISRSEMLEIVqaiykmvssvmkMPEDESTPEKRTDKIFRQMDTNNDGKLSLEEFI 170
Cdd:cd16227   213 LDGEEILSWL------------VPDNEEIAEEEVDHLFASADDDHDDRLSFDEIL 255

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1622854142  68 VFRTFDTNGDGTIDFREFIIALSVTSRGK--LEQKLKWAFSMYDLDGNGYISRSEMLEIVQ 126
Cdd:pfam13499   7 AFKLLDSDGDGYLDVEELKKLLRKLEEGEplSDEEVEELFKEFDLDKDGRISFEEFLELYS 67

EF-hand-like motif found in the dystrophin/dystrobrevin/dystrotelin family; The dystrophin/dystrobrevin/dystrotelin family has been characterized by a compact cluster of domains comprising four EF-hand-like motifs and a ZZ-domain, followed by a looser region with two coiled-coils. Dystrophin is the founder member of this family. It is a sub-membrane cytoskeletal protein associated with the inner surface membrane. Dystrophin and its close paralog utrophin have a large N-terminal extension of actin-binding CH domains, up to 24 spectrin repeats, and a WW domain. Its further paralog, dystrophin-related protein 2 (DRP-2), retains only two of the spectrin repeats. Dystrophin, utrophin or DRP2 can form the core of a membrane-bound complex consisting of dystroglycan, sarcoglycans and syntrophins, known as the dystrophin-glycoprotein complex (DGC) that plays an important role in brain development and disease, as well as in the prevention of muscle damage. Dystrobrevins, including alpha- and beta-dystrobrevin, lack the large N-terminal extension found in dystrophin, but alpha-dystrobrevin has a characteristic C-terminal extension. Dystrobrevins are part of the DGC. They physically associate with members of the dystrophin family and with the syntrophins through their homologous C-terminal coiled coil motifs. In contrast, dystrotelins lack both the large N-terminal extension found in dystrophin and the obvious syntrophin-binding sites (SBSs). Dystrotelins are not critical for mammalian development. They may be involved in other forms of cytokinesis. Moreover, dystrotelin is unable to heterodimerize with members of the dystrophin or dystrobrevin families, or to homodimerize.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1622854142  71 TFDTNGDGTIDFREFIIALSVTSRGKLEQKLKWAFSMYDlDGNGYISRSEMLEIVQAIYKMVS 133
Cdd:cd15901    62 LYDRNRTGCIRLLSVKIALITLCAASLLDKYRYLFGQLA-DSSGFISRERLTQFLQDLLQIPD 123

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 1622854142  100 KLKWAFSMYDLDGNGYISRSEMLEIVQAI 128
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

Eps15 homology domain; found in proteins implicated in endocytosis, vesicle transport, and signal transduction. The alignment contains a pair of EF-hand motifs, typically one of them is canonical and binds to Ca2+, while the other may not bind to Ca2+. A hydrophobic binding pocket is formed by residues from both EF-hand motifs. The EH domain binds to proteins containing NPF (class I), [WF]W or SWG (class II), or H[TS]F (class III) sequence motifs.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1622854142 105 FSMYDLDGNGYISRSEMLEIvqaiykMVSSvmKMPEDEstpekrTDKIFRQMDTNNDGKLSLEEFI 170
Cdd:cd00052     5 FRSLDPDGDGLISGDEARPF------LGKS--GLPRSV------LAQIWDLADTDKDGKLDKEEFA 56

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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622854142  64 FAEHVFRTFDTNGDGTIDFREFIIALSVTSRGKLEQKLKWA-----------FSMYDLDGNGYISRSEM-------LEIV 125
Cdd:cd16179   142 YTDTILQLFDRNKDGKLQLSEMARLLPVKENFLCRPIFKGAgkltredidrvFALYDRDNNGTIENEELtgflkdlLELV 221

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1622854142 126 QAIYkmvssvmkmpeDESTPEKRTDKIFRQMDTNNDGKLSLEE 168
Cdd:cd16179   222 QEDY-----------DEQDLEEFKEIILRGWDFNNDGKISRKE 253

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 1622854142  70 RTFDTNGDGTIDFREFIiALSVTSRGKlEQKLKWAFS-------MYDLDGNGYISRSEMLEIVqaiykmvssvmkMPEDE 142
Cdd:cd15899   167 EDLDKNGDGFISLEEFI-SDPYSADEN-EEEPEWVKVekerfveLRDKDKDGKLDGEELLSWV------------DPSNQ 232

                          90       100
                  ....*....|....*....|....*....
gi 1622854142 143 STPEKRTDKIFRQMDTNNDGKLSLEEFIK 171
Cdd:cd15899   233 EIALEEAKHLIAESDENKDGKLSPEEILD 261

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 1622854142 105 FSMYDLDGNGYISRSEMLEIVQAIYKMVSSvMKMPEDESTPEKRTdkIFRQMDTNNDGKLSLEEFIKGAKSDPSIVRLLQ 184
Cdd:cd15902     5 WMHFDADGNGYIEGKELDSFLRELLKALNG-KDKTDDEVAEKKKE--FMEKYDENEDGKIEIRELANILPTEENFLLLFR 81

                  ....*...
gi 1622854142 185 CDPSSASQ 192
Cdd:cd15902    82 REQPLISS 89

EF-hand domain pair;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1622854142  39 PTGHLTVDEFKKIYANFFPYGDASKFAEHVFRTFDTNGDGTIDFREFIIAL 89
Cdd:pfam13833   1 EKGVITREELKRALALLGLKDLSEDEVDILFREFDTDGDGYISFDEFCVLL 51

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
                  ....*....|....*....|....*....|....*....|....*....
gi 1622854142  43 LTVDEFKKIY----ANFFPYGDASKFAEHVFRTFDTNGDGTIDFREFII 87
Cdd:cd05030    27 LYKKEFKQLVekelPNFLKKEKNQKAIDKIFEDLDTNQDGQLSFEEFLV 75

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 1622854142  24 DHELQEWYKGFLKDCPTGHLTVDEFKKIYANFFpygdaskfaehvfRTFDTNGDGTIDFRE----------FIIALSVTS 93
Cdd:cd15902    18 GKELDSFLRELLKALNGKDKTDDEVAEKKKEFM-------------EKYDENEDGKIEIRElanilpteenFLLLFRREQ 84

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1622854142  94 RGKLEQKLKWAFSMYDLDGNGYISRSEMleivQAIYKMVSSVMKMPEDESTPEKRTDKIFRQMDTNNDGKLSLEEFIK 171
Cdd:cd15902    85 PLISSVEFMKIWRKYDTDGSGFIEAKEL----KGFLKDLLLKNKKHVSPPKLDEYTKLILKEFDANKDGKLELDEMAK 158

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 1622854142  73 DTNGDGTIDFREFI--IALSVTSRGKLEQKLKwaFSMYDLDGNGYISRSEmleIVQAIYKMVSSVMKMPEDESTPEKRT- 149
Cdd:cd16227    46 DLNDDGFIDRKELKawILRSFKMLDEEEANER--FEEADEDGDGKVTWEE---YLADSFGYDDEDNEEMIKDSTEDDLKl 120

                          90       100
                  ....*....|....*....|....*.
gi 1622854142 150 ---DKI-FRQMDTNNDGKLSLEEFIK 171
Cdd:cd16227   121 ledDKEmFEAADLNKDGKLDKTEFSA 146

EF-hand, calcium binding motif, found in peflin and similar proteins; Peflin, also termed penta-EF hand (PEF) protein with a long N-terminal hydrophobic domain, or penta-EF hand domain-containing protein 1, 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+. In lower vertebrates, peflin may interact with transient receptor potential N (TRPN1), suggesting a potential role of peflin in fast transducer channel adaptation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622854142  26 ELQEWYKGFLKDcPTGHLTVDEFKKIYANffpyGDASKFAEH----VFRTFDTNGDGTIDFREFiialsvTSRGKLEQKL 101
Cdd:cd16184     1 EVQQWFQAVDRD-RSGKISAKELQQALVN----GNWSHFNDEtcrlMIGMFDKDKSGTIDIYEF------QALWNYIQQW 69

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622854142 102 KWAFSMYDLDGNGYISRSEMleiVQAIYKM--------VSSVM---------KMPEDE----STPEKRTDKIFRQMDTNN 160
Cdd:cd16184    70 KQVFQQFDRDRSGSIDENEL---HQALSQMgyrlspqfVQFLVskydprarrSLTLDQfiqvCVQLQSLTDAFRQRDTQM 146

                         170
                  ....*....|..
gi 1622854142 161 DG--KLSLEEFI 170
Cdd:cd16184   147 TGtiTISYEDFL 158

EF-hand, calcium binding motif, found in mitochondrial calcium uptake proteins MICU1, MICU2, MICU3, and similar proteins; This family includes mitochondrial calcium uptake protein MICU1 and its two additional paralogs, MICU2 and MICU3. MICU1 localizes to the inner mitochondrial membrane (IMM). It functions as a gatekeeper of the mitochondrial calcium uniporter (MCU) and regulates MCU-mediated mitochondrial Ca2+ uptake, which is essential for maintaining mitochondrial homoeostasis. MICU1 and MICU2 are physically associated within the uniporter complex and are co-expressed across all tissues. They may play non-redundant roles in the regulation of the mitochondrial calcium uniporter. At present, the precise molecular function of MICU2 and MICU3 remain unclear. MICU2 may play possible roles in Ca2+ sensing and regulation of MCU, calcium buffering with a secondary impact on transport or assembly and stabilization of MCU. MICU3 likely has a role in mitochondrial calcium handling. All members in this family contains an N-terminal mitochondrial targeting sequence (MTS) as well as two evolutionarily conserved canonical Ca2+-binding EF-hands separated by a long stretch of residues predicted to form alpha-helices.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1622854142 104 AFSMYDLDGNGYISRSEMLEIVQAIYKMVSSVMKmpedeSTPEKRTDKIFRQMDT---------NNDGKLSLEEFIK 171
Cdd:cd15900     5 AFKMFDLDGDGELDKEEFNKVQSIIRSQTSVGQR-----HRDHTNGESTKLGMNStlaryffgkDGKQKLSIEKFLE 76

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 1622854142  150 DKIFRQMDTNNDGKLSLEEFIKGAKS 175
Cdd:smart00054   3 KEAFRLFDKDGDGKIDFEEFKDLLKA 28

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1622854142 100 KLKWAFSMYDLDGNGYISRSEMLEIVQAIykmvssvmkmpeDESTPEKRTDKIFRQMDTNNDGKLSLEEFIK 171
Cdd:cd15898     1 WLRRQWIKADKDGDGKLSLKEIKKLLKRL------------NIRVSEKELKKLFKEVDTNGDGTLTFDEFEE 60

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1622854142 104 AFSMYDLDGNGYISRSEMLEIVQAIYKMVssvmKMPEDESTPEKRTDKIFRQMDTNNDGKLSLEE 168
Cdd:cd16176    90 TWRKYDADHSGFIEADELKSFLKDLLKKA----NKPFDESKLEEYTHTMLKMFDSNNDGKLGLTE 150

EF-hand, calcium binding motif, found in apoptosis-linked gene 2 protein (ALG-2) and similar proteins; ALG-2, also termed programmed cell death protein 6 (PDCD6), or probable calcium-binding protein ALG-2, is one of the prototypic members of the penta EF-hand protein family. It is a widely expressed calcium-binding modulator protein associated with cell proliferation and death, as well as cell survival. ALG-2 acts as a pro-apoptotic factor participating in T cell receptor-, Fas-, and glucocorticoid-induced programmed cell death, and also serves as a useful molecular marker for the prognosis of cancers. Moreover, ALG-2 functions as a calcium ion sensor at endoplasmic reticulum (ER) exit sites, and modulates ER-stress-stimulated cell death and neuronal apoptosis during organ formation. Furthermore, ALG-2 can mediate the pro-apoptotic activity of cisplatin or tumor necrosis factor alpha (TNFalpha) through the down-regulation of nuclear factor-kappaB (NF-kappaB) expression. It also inhibits angiogenesis through PI3K/mTOR/p70S6K pathway by interacting of vascular endothelial growth factor receptor-2 (VEGFR-2). In addition, nuclear ALG-2 may participate in the post-transcriptional regulation of Inositol Trisphosphate Receptor Type 1 (IP3R1) pre-mRNA at least in part by interacting with CHERP (Ca2+ homeostasis endoplasmic reticulum protein) calcium-dependently. ALG-2 contains five serially repeated EF-hand motifs and interacts with various proteins, including ALG-2-interacting protein X (Alix), Fas, annexin XI, death-associated protein kinase 1 (DAPk1), Tumor susceptibility gene 101 (TSG101), Sec31A, phospholipid scramblase 3 (PLSCR3), the P-body component PATL1, and endosomal sorting complex required for transport (ESCRT)-III-related protein IST1, in a calcium-dependent manner. 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622854142  26 ELQEWYKGFLKDcPTGHLTVDEFKKIYANffpyGDASKFAEHVFRT----FDTNGDGTIDFREFiialsvTSRGKLEQKL 101
Cdd:cd16183     1 FLWNVFQRVDKD-RSGQISATELQQALSN----GTWTPFNPETVRLmigmFDRDNSGTINFQEF------AALWKYITDW 69

                          90       100
                  ....*....|....*....|
gi 1622854142 102 KWAFSMYDLDGNGYISRSEM 121
Cdd:cd16183    70 QNCFRSFDRDNSGNIDKNEL 89

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 1622854142  62 SKFA-EHVFRTFDTNGDGTIDFREFIIALSVTSRGK------LEQKLKWAfSMYDLDGNGYISRSEMLEIVqaiykmvss 134
Cdd:cd16224   159 TEFViQEALEEHDKDGDGFISLEEFLGDYRKDPTANedpewiIVEKDRFV-NDYDKDNDGKLDPQELLPWV--------- 228

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 1622854142 135 vmkMPEDESTPEKRTDKIFRQMDTNNDGKLSLEEFIK 171
Cdd:cd16224   229 ---VPNNYGIAQEEALHLIDEMDLNGDGRLSEEEILE 262

EF-hand, calcium binding motif, found in calretinin (CR); CR, also termed 29 kDa calbindin, 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 possibly functions as a calcium buffer, calcium sensor, and apoptosis regulator, which may be implicated in many biological processes, including cell proliferation, differentiation, and cell death. CR contains six EF-hand motifs within two independent domains, CR I-II and CR III-VI. CR I-II consists of EF-hand motifs 1 and 2, and CR III-VI consists of EF-hand motifs 3-6. The first 5 EF-hand motifs are capable of binding calcium ions, while the EF-hand 6 is inactive. Thus, CR has two pairs of cooperative binding sites (I-II and III-IV), which display high affinity calcium-binding sites, and one independent calcium ion-binding site (V), which displays lower affinity binding.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622854142  63 KFAEHV---FRTFDTNGDGTIDFREFIIALSVTSRGKL--------EQKLKWAFSMYDLDGNGYISRSEMLEIVQAIYKM 131
Cdd:cd16177    43 NFGEKMkefMQKYDKNADGRIEMAELAQILPTEENFLLcfrqhvgsSSEFMEAWRKYDTDRSGYIEANELKGFLSDLLKK 122

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1622854142 132 VSSvmkmPEDESTPEKRTDKIFRQMDTNNDGKLSLEEFIK 171
Cdd:cd16177   123 ANR----PYDEKKLQEYTQTILRMFDLNGDGKLGLSEMAR 158

EF-hand, calcium binding motif, found in calretinin (CR); CR, also termed 29 kDa calbindin, 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 possibly functions as a calcium buffer, calcium sensor, and apoptosis regulator, which may be implicated in many biological processes, including cell proliferation, differentiation, and cell death. CR contains six EF-hand motifs within two independent domains, CR I-II and CR III-VI. CR I-II consists of EF-hand motifs 1 and 2, and CR III-VI consists of EF-hand motifs 3-6. The first 5 EF-hand motifs are capable of binding calcium ions, while the EF-hand 6 is inactive. Thus, CR has two pairs of cooperative binding sites (I-II and III-IV), which display high affinity calcium-binding sites, and one independent calcium ion-binding site (V), which displays lower affinity binding.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622854142  40 TGHLTVDEFKKIYANFF-----PYGDAS--KFAEHVFRTFDTNGDGTIDFREFIIALSVTSRGKLE-QKLKWA------- 104
Cdd:cd16177   104 SGYIEANELKGFLSDLLkkanrPYDEKKlqEYTQTILRMFDLNGDGKLGLSEMARLLPVQENFLLKfQGMKLSseefnai 183

                          90       100
                  ....*....|....*....|....*.
gi 1622854142 105 FSMYDLDGNGYISRSEMLEIVQAIYK 130
Cdd:cd16177   184 FAFYDKDGSGYIDENELDALLKDLYE 209

EF-hand, calcium binding motif, found in uncharacterized calglandulin-like proteins; The family corresponds to a group of uncharacterized calglandulin-like proteins. Although their biological function remain unclear, they show high sequence similarity with human calglandulin-like protein GAGLP, which is an ortholog of calglandulin from the venom glands of Bothrops insularis snake. Both GAGLP and calglandulin are putative Ca2+-binding proteins with four EF-hand motifs. However, members in this family contain only three EF-hand motifs. In this point, they may belong to the parvalbumin-like EF-hand family, which is characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622854142  91 VTSRGKLEQKLKWAFSMYDLDGNGYISRSEMLEIVQAIykmVSSVMKMP-EDEstpekRTDKIFRQMDTNNDGKLSLEEF 169
Cdd:cd16252    29 FQTSEQQEEAIRKAFQMLDKDKSGFIEWNEIKYILSTV---PSSMPVAPlSDE-----EAEAMIQAADTDGDGRIDFQEF 100

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 1622854142  14 QDLRENTEFtdheLQEWYKgFLKDcPTGHLTVDEFKKIYANFF-----PYgDASKFAEH---VFRTFDTNGDGTIDFREF 85
Cdd:cd16176    79 QQLKSSEEF----MQTWRK-YDAD-HSGFIEADELKSFLKDLLkkankPF-DESKLEEYthtMLKMFDSNNDGKLGLTEM 151

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 1622854142  86 IIALSVTSRGKLE-QKLKW-------AFSMYDLDGNGYISRSEM 121
Cdd:cd16176   152 ARLLPVQENFLLKfQGVKMcgkefnkIFELYDQDGNGYIDENEL 195

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 1622854142  68 VFRTFDTNGDGTIDFREFIIALSVTSRGKLEQKLKWAFSMYDLDGNGYISRSEMLEIVQAIYKMVSSVMKMPEDESTPEK 147
Cdd:cd16226    40 IVDKIDKNGDGFVTEEELKDWIKYVQKKYIREDVDRQWKEYDPNKDGKLSWEEYKKATYGFLDDEEEDDDLHESYKKMIR 119

                          90       100
                  ....*....|....*....|..
gi 1622854142 148 RTDKIFRQMDTNNDGKLSLEEF 169
Cdd:cd16226   120 RDERRWKAADQDGDGKLTKEEF 141

EF hand;

                          10        20
                  ....*....|....*....|
gi 1622854142  66 EHVFRTFDTNGDGTIDFREF 85
Cdd:pfam13202   2 KDTFRQIDLNGDGKISKEEL 21

EF-hand domain;

                          10        20
                  ....*....|....*....|....
gi 1622854142  66 EHVFRTFDTNGDGTIDFREFIIAL 89
Cdd:pfam13405   3 REAFKLFDKDGDGKISLEELRKAL 26

EF-hand domain;

                          10        20
                  ....*....|....*....|....*
gi 1622854142 151 KIFRQMDTNNDGKLSLEEFIKGAKS 175
Cdd:pfam13405   4 EAFKLFDKDGDGKISLEELRKALRS 28