EF-hand, calcium binding motif, found in parvalbumin-like EF-hand family; The family includes alpha- and beta-parvalbumins, and a group of uncharacterized calglandulin-like proteins. Parvalbumins are small, acidic, cytosolic EF-hand-containing Ca2+-buffer and Ca2+ transporter/shuttle proteins belonging to EF-hand superfamily. They are expressed by vertebrates in fast-twitch muscle cells, specific neurons of the central and peripheral nervous system, sensory cells of the mammalian auditory organ (Corti's cell), and some other cells, and 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+. Thus, they may play an additional role in Mg2+ handling. Moreover, parvalbumins represent one of the major animal allergens. In metal-bound states, parvalbumins possess a rigid and stable tertiary structure and display strong allergenicity. In contrast, the metal-free parvalbumins are intrinsically disordered, and the loss of metal ions results in a conformational change that decreases their IgE binding capacity. Furthermore, parvalbumins have been widely used as a neuronal marker for a variety of functional brain systems. They also function as a Ca2+ shuttle transporting Ca2+ from troponin-C (TnC) to the sarcoplasmic reticulum (SR) Ca2+ pump during muscle relaxation. Thus they may facilitate myocardial relaxation and play important roles in cardiac diastolic dysfunction. Parvalbumins consists of alpha- and beta- sublineages, which can be distinguished on the basis of isoelectric point (pI > 5 for alpha; pI

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 46391079  10 DDIAAAMQACQAQGSFNHESFFEQVGLIGRASSDGEKVFKALDQDKSGYIEKEELKRFLQNFCSKARELTEAETNTLLAA 89
Cdd:cd16255   2 ADIAAALSQCQAADSFNFKKFFATSGLSKKSADDVKKVFEIIDQDKSGFIEEEELKLFLQNFSSGARELTDAETKAFLKA 81

                        90
                ....*....|....*....
gi 46391079  90 GDKDGDGKIGIEEFCALLK 108
Cdd:cd16255  82 GDSDGDGKIGVEEFQALVK 100

EF-hand, calcium binding motif, found in beta-parvalbumin; Beta-parvalbumin, also termed Oncomodulin-1 (OM), is a small calcium-binding protein that is expressed in hepatomas, as well as in the blastocyst and the cytotrophoblasts of the placenta. It is also found to be expressed in the cochlear outer hair cells of the organ of Corti and frequently expressed in neoplasms. Mammalian beta-parvalbumin is secreted by activated macrophages and neutrophils. It may function as a tissue-specific Ca2+-dependent regulatory protein, and may also serve as a specialized cytosolic Ca2+ buffer. Beta-parvalbumin acts as a potent growth-promoting signal between the innate immune system and neurons in vivo. It has high and specific affinity for its receptor on retinal ganglion cells (RGC) and functions as the principal mediator of optic nerve regeneration. It exerts its effects in a cyclic adenosine monophosphate (cAMP)-dependent manner and can further elevate intracellular cAMP levels. Moreover, beta-parvalbumin is associated with efferent function and outer hair cell electromotility, and can identify different hair cell types in the mammalian inner ear. Beta-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+. The EF site displays a high-affinity for Ca2+/Mg2+, and the CD site is a low-affinity Ca2+-specific site. In addition, beta-parvalbumin is distinguished from other parvalbumins by its unusually low isoelectric point (pI = 3.1) and sequence eccentricities (e.g., Y57-L58-D59 instead of F57-I58-E59).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 46391079  10 DDIAAAMQACQAQGSFNHESFFEQVGLIGRASSDGEKVFKALDQDKSGYIEKEELKRFLQNFCSKARELTEAETNTLLAA 89
Cdd:cd16255   2 ADIAAALSQCQAADSFNFKKFFATSGLSKKSADDVKKVFEIIDQDKSGFIEEEELKLFLQNFSSGARELTDAETKAFLKA 81

                        90
                ....*....|....*....
gi 46391079  90 GDKDGDGKIGIEEFCALLK 108
Cdd:cd16255  82 GDSDGDGKIGVEEFQALVK 100

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

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 46391079  45 EKVFKALDQDKSGYIEKEELKRFLqnfcsKARELTEAETNTLLAAGDKDGDGKIGIEEFCALLK 108
Cdd:COG5126  72 RAAFDLLDTDGDGKISADEFRRLL-----TALGVSEEEADELFARLDTDGDGKISFEEFVAAVR 130

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 46391079   40 ASSDGEKVFKALDQDKSGYIEKEELKRFLQNFCSkareltEAETNTLLAAGDKDGDGKIGIEEFCALLK 108
Cdd:NF041410 101 STELADDLLSALDTDGDGSISSDELSAGLTSAGS------SADSSQLFSALDSDGDGSVSSDELAAALQ 163

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 46391079   41 SSDGEKVFKALDQDKSGYIEKEELKRFL------QNFcSKARELTEAetntLLAAGDKDGDGKIGIEEFCALL 107
Cdd:NF041410  62 LIDLSELFSDLDSDGDGSLSSDELAAAAppppppPDQ-APSTELADD----LLSALDTDGDGSISSDELSAGL 129

EF-hand, calcium binding motif, found in beta-parvalbumin; Beta-parvalbumin, also termed Oncomodulin-1 (OM), is a small calcium-binding protein that is expressed in hepatomas, as well as in the blastocyst and the cytotrophoblasts of the placenta. It is also found to be expressed in the cochlear outer hair cells of the organ of Corti and frequently expressed in neoplasms. Mammalian beta-parvalbumin is secreted by activated macrophages and neutrophils. It may function as a tissue-specific Ca2+-dependent regulatory protein, and may also serve as a specialized cytosolic Ca2+ buffer. Beta-parvalbumin acts as a potent growth-promoting signal between the innate immune system and neurons in vivo. It has high and specific affinity for its receptor on retinal ganglion cells (RGC) and functions as the principal mediator of optic nerve regeneration. It exerts its effects in a cyclic adenosine monophosphate (cAMP)-dependent manner and can further elevate intracellular cAMP levels. Moreover, beta-parvalbumin is associated with efferent function and outer hair cell electromotility, and can identify different hair cell types in the mammalian inner ear. Beta-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+. The EF site displays a high-affinity for Ca2+/Mg2+, and the CD site is a low-affinity Ca2+-specific site. In addition, beta-parvalbumin is distinguished from other parvalbumins by its unusually low isoelectric point (pI = 3.1) and sequence eccentricities (e.g., Y57-L58-D59 instead of F57-I58-E59).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 46391079  10 DDIAAAMQACQAQGSFNHESFFEQVGLIGRASSDGEKVFKALDQDKSGYIEKEELKRFLQNFCSKARELTEAETNTLLAA 89
Cdd:cd16255   2 ADIAAALSQCQAADSFNFKKFFATSGLSKKSADDVKKVFEIIDQDKSGFIEEEELKLFLQNFSSGARELTDAETKAFLKA 81

                        90
                ....*....|....*....
gi 46391079  90 GDKDGDGKIGIEEFCALLK 108
Cdd:cd16255  82 GDSDGDGKIGVEEFQALVK 100

EF-hand, calcium binding motif, found in parvalbumins; Parvalbumins are small, acidic, cytosolic EF-hand-containing Ca2+-buffer and Ca2+ transporter/shuttle proteins belonging to EF-hand superfamily. They are expressed by vertebrates in fast-twitch muscle cells, specific neurons of the central and peripheral nervous system, sensory cells of the mammalian auditory organ (Corti's cell), and some other cells, and 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+. Thus, they may play an additional role in Mg2+ handling. Moreover, parvalbumins represent one of the major animal allergens. In metal-bound states, parvalbumins possess a rigid and stable tertiary structure and display strong allergenicity. In contrast, the metal-free parvalbumins are intrinsically disordered, and the loss of metal ions results in a conformational change that decreases their IgE binding capacity. Furthermore, parvalbumins have been widely used as a neuronal marker for a variety of functional brain systems. They also function as a Ca2+ shuttle transporting Ca2+ from troponin-C (TnC) to the sarcoplasmic reticulum (SR) Ca2+ pump during muscle relaxation. Thus they may facilitate myocardial relaxation and play important roles in cardiac diastolic dysfunction. Parvalbumins consists of alpha- and beta- sublineages, which can be distinguished on the basis of isoelectric point (pI > 5 for alpha; pI

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 46391079  11 DIAAAMQACQAQGSFNHESFFEQVGLIGRASSDGEKVFKALDQDKSGYIEKEELKRFLQNFCSKARELTEAETNTLLAAG 90
Cdd:cd16253   3 DIDIALAACQAADSFDHKAFFKAVGLSKKSPADIKKVFNILDQDKSGFIEEEELKLFLKNFSDGARVLSDKETKNFLAAG 82

                        90
                ....*....|....*...
gi 46391079  91 DKDGDGKIGIEEFCALLK 108
Cdd:cd16253  83 DSDGDGKIGVDEFKSMVK 100

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 46391079  23 GSFNHESFFE---QVGLIGRASSDGEKVFKALDQDKSGYIEKEELKRFLQNFCSK--ARELTEAETNTLLAAGDKDGDGK 97
Cdd:cd16252  15 GSFNYSKFFEymqKFQTSEQQEEAIRKAFQMLDKDKSGFIEWNEIKYILSTVPSSmpVAPLSDEEAEAMIQAADTDGDGR 94

                        90
                ....*....|.
gi 46391079  98 IGIEEFCALLK 108
Cdd:cd16252  95 IDFQEFSDMVK 105

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 46391079    47 VFKALDQDKSGYIEKEELKRFLQNFCsKARELTEAETNTLLAAGDKDGDGKIGIEEFCALLK 108
Cdd:pfam13499   7 AFKLLDSDGDGYLDVEELKKLLRKLE-EGEPLSDEEVEELFKEFDLDKDGRISFEEFLELYS 67

EF-hand, calcium binding motif, found in the hexa-EF hand proteins family; The hexa-EF hand proteins family, also named the calbindin sub-family, contains a group of six EF-hand Ca2+-binding proteins, including calretinin (CR, also termed 29 kDa calbindin), calbindin D28K (CB, also termed vitamin D-dependent calcium-binding protein, avian-type), and secretagogin (SCGN). CR is a cytosolic hexa-EF-hand calcium-binding protein predominantly expressed in a variety of normal and tumorigenic t-specific neurons of the central and peripheral nervous system. It is a multifunctional protein implicated in many biological processes, including cell proliferation, differentiation, and cell death. CB is highly expressed in brain tissue. It is a strong calcium-binding and buffering protein responsible for preventing a neuronal death as well as maintaining and controlling calcium homeostasis. SCGN is a six EF-hand calcium-binding protein expressed in neuroendocrine, pancreatic endocrine and retinal cells. It plays a crucial role in cell apoptosis, receptor signaling and differentiation. It is also involved in vesicle secretion through binding to various proteins, including interacts with SNAP25, SNAP23, DOC2alpha, ARFGAP2, rootletin, KIF5B, beta-tubulin, DDAH-2, ATP-synthase and myeloid leukemia factor 2. SCGN functions as a Ca2+ sensor/coincidence detector modulating vesicular exocytosis of neurotransmitters, neuropeptides or hormones. Although the family members share a significant amount of secondary sequence homology, they display altered structural and biochemical characteristics, and operate in distinct fashions. CB contains six EF-hand motifs in a single globular domain, where EF-hands 1, 3, 4, 5 bind four calcium ions. CR contains six EF-hand motifs within two independent domains, CR I-II and CR III-VI. They harbor two and four EF-hand motifs, respectively. The first 5 EF-hand motifs are capable of binding calcium ions, while the EF-hand 6 is inactive. SCGN consists of the three globular domains each of which contains a pair of EF-hand motifs. Human SCGN simultaneously binds four calcium ions through its EF-hands 3, 4, 5 and 6 in one high affinity and three low affinity calcium-binding sites. In contrast, SCGNs in other lower eukaryotes, such as D. rerio, X. laevis, M. domestica, G. gallus, O. anatinus, are fully competent in terms of six calcium-binding.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 46391079  46 KVFKALDQDKSGYIEKEELKRFLQNFCSKAREL-----TEAETNTLLAAGDKDGDGKIGIEEFCALL 107
Cdd:cd15902  94 KIWRKYDTDGSGFIEAKELKGFLKDLLLKNKKHvsppkLDEYTKLILKEFDANKDGKLELDEMAKLL 160

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
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 46391079  47 VFKALDQDKSGYIEKEELKRFLQNFC-SKARELTeaeTNTLLAAGDKDGDGKIGIEEFCALLK 108
Cdd:cd16180   5 IFQAVDRDRSGRISAKELQRALSNGDwTPFSIET---VRLMINMFDRDRSGTINFDEFVGLWK 64

EF-hand, calcium binding motif, found in secretagogin (SCGN); SCGN is a six EF-hand calcium-binding protein expressed in neuroendocrine, pancreatic endocrine and retinal cells. It plays a crucial role in cell apoptosis, receptor signaling and differentiation. It is also involved in vesicle secretion through binding to various proteins, including interacts with SNAP25, SNAP23, DOC2alpha, ARFGAP2, rootletin, KIF5B, beta-tubulin, DDAH-2, ATP-synthase and myeloid leukemia factor 2. SCGN functions as a calcium sensor/coincidence detector modulating vesicular exocytosis of neurotransmitters, neuropeptides or hormones. It also serves as a calcium buffer in neurons. Thus, SCGN may be linked to the pathogenesis of neurological diseases such as Alzheimer's, and also acts as a serum marker of neuronal damage, or as a tumor biomarker. SCGN consists of the three globular domains each of which contains a pair of EF-hand motifs. All six EF hand motifs of SCGN in some eukaryotes, including D. rerio, X. laevis, M. domestica, G. gallus, O. anatinus, could potentially bind six calcium ions. In contrast, SCGNs from higher eukaryotes have at least one non-functional EF-hand motif due to the mutation(s) or deletions. For instance, the EF1 loop does not coordinate calcium ion due to the key residue asparagine replaced by lysine in SCGNs of many mammalian species. Moreover, the EF2 loop seems to be competent for calcium-binding in most mammalian SCGNs except for human and chimpanzee orthologs.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 46391079  46 KVFKALDQDKSGYIEKEELKRFLQNFC-SKARELTEAE----TNTLLAAGDKDGDGKIGIEEFCALL 107
Cdd:cd16178  96 RIWRKYDADSSGYISAAELKNFLRDLFlQHKKVITEDKldeyTDTMMKIFDKNKDGRLDLNDMARIL 162

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 46391079  25 FNHESFFEQVGLIGR---ASSDGEKVFKALDQDKSGYIEKEELKRFLQNFCSKARELTEAET-----NTLLAAGDKDGDG 96
Cdd:cd15902 161 PVQENFLLKFQILGAmdlTKEDFEKVFEHYDKDNNGVIEGNELDALLKDLLEKNKADIDKPDlenfrDAILRACDKNKDG 240

                        90
                ....*....|..
gi 46391079  97 KIGIEEFCALLK 108
Cdd:cd15902 241 KIQKTELALFLS 252

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 46391079  39 RASSDGEKVFKALDQDKSGYIEKEELKRFLQNFCSKARELTEAE-----TNTLLAAGDKDGDGKIGIEEFCALL 107
Cdd:cd16176  82 KSSEEFMQTWRKYDADHSGFIEADELKSFLKDLLKKANKPFDESkleeyTHTMLKMFDSNNDGKLGLTEMARLL 155

EF-hand, calcium binding motif, found in the hexa-EF hand proteins family; The hexa-EF hand proteins family, also named the calbindin sub-family, contains a group of six EF-hand Ca2+-binding proteins, including calretinin (CR, also termed 29 kDa calbindin), calbindin D28K (CB, also termed vitamin D-dependent calcium-binding protein, avian-type), and secretagogin (SCGN). CR is a cytosolic hexa-EF-hand calcium-binding protein predominantly expressed in a variety of normal and tumorigenic t-specific neurons of the central and peripheral nervous system. It is a multifunctional protein implicated in many biological processes, including cell proliferation, differentiation, and cell death. CB is highly expressed in brain tissue. It is a strong calcium-binding and buffering protein responsible for preventing a neuronal death as well as maintaining and controlling calcium homeostasis. SCGN is a six EF-hand calcium-binding protein expressed in neuroendocrine, pancreatic endocrine and retinal cells. It plays a crucial role in cell apoptosis, receptor signaling and differentiation. It is also involved in vesicle secretion through binding to various proteins, including interacts with SNAP25, SNAP23, DOC2alpha, ARFGAP2, rootletin, KIF5B, beta-tubulin, DDAH-2, ATP-synthase and myeloid leukemia factor 2. SCGN functions as a Ca2+ sensor/coincidence detector modulating vesicular exocytosis of neurotransmitters, neuropeptides or hormones. Although the family members share a significant amount of secondary sequence homology, they display altered structural and biochemical characteristics, and operate in distinct fashions. CB contains six EF-hand motifs in a single globular domain, where EF-hands 1, 3, 4, 5 bind four calcium ions. CR contains six EF-hand motifs within two independent domains, CR I-II and CR III-VI. They harbor two and four EF-hand motifs, respectively. The first 5 EF-hand motifs are capable of binding calcium ions, while the EF-hand 6 is inactive. SCGN consists of the three globular domains each of which contains a pair of EF-hand motifs. Human SCGN simultaneously binds four calcium ions through its EF-hands 3, 4, 5 and 6 in one high affinity and three low affinity calcium-binding sites. In contrast, SCGNs in other lower eukaryotes, such as D. rerio, X. laevis, M. domestica, G. gallus, O. anatinus, are fully competent in terms of six calcium-binding.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 46391079  46 KVFKALDQDKSGYIEKEELKRFLQNFCSKARELTEAETN------TLLAAGDKDGDGKIGIEEFCALL 107
Cdd:cd15902   3 EVWMHFDADGNGYIEGKELDSFLRELLKALNGKDKTDDEvaekkkEFMEKYDENEDGKIEIRELANIL 70

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
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 46391079  48 FKALDQDKSGYIEKEELKRFLQNFcsKARELTEAETNTLLAAGDKDGDGKIGIEEFCAL 106
Cdd:cd16184   6 FQAVDRDRSGKISAKELQQALVNG--NWSHFNDETCRLMIGMFDKDKSGTIDIYEFQAL 62

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 46391079   40 ASSDGEKVFKALDQDKSGYIEKEELKRFLQNFCSkareltEAETNTLLAAGDKDGDGKIGIEEFCALLK 108
Cdd:NF041410 101 STELADDLLSALDTDGDGSISSDELSAGLTSAGS------SADSSQLFSALDSDGDGSVSSDELAAALQ 163

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
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 46391079  47 VFKALDQDKSGYIEKEELKRFLQNfcSKARELTEAETNTLLAAGDKDGDGKIGIEEFCALLK 108
Cdd:cd16183   5 VFQRVDKDRSGQISATELQQALSN--GTWTPFNPETVRLMIGMFDRDNSGTINFQEFAALWK 64

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 46391079   45 EKVFKALDQDKSGYIEKEELKRFLQnfcSKARELTEAETNTLLAAGDKDGDGKIGIEEFCALLK 108
Cdd:NF041410  30 KQLFAKLDSDGDGSVSQDELSSALS---SKSDDGSLIDLSELFSDLDSDGDGSLSSDELAAAAP 90

centrin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 46391079   23 GSFNHESFFE--QVGLIGRASSDG-EKVFKALDQDKSGYIEKEELKRFLQNFcskARELTEAETNTLLAAGDKDGDGKIG 99
Cdd:PTZ00183  68 GKIDFEEFLDimTKKLGERDPREEiLKAFRLFDDDKTGKISLKNLKRVAKEL---GETITDEELQEMIDEADRNGDGEIS 144

                 ....*....
gi 46391079  100 IEEFCALLK 108
Cdd:PTZ00183 145 EEEFYRIMK 153

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 46391079  48 FKALDQDKSGYIEKEELKRFLqnfcSKAR-ELTEAETNTLLAAGDKDGDGKIGIEEFCAL 106
Cdd:cd16185   6 FRAVDRDRSGSIDVNELQKAL----AGGGlLFSLATAEKLIRMFDRDGNGTIDFEEFAAL 61

EF hand;

                          10        20
                  ....*....|....*....|....
gi 46391079    45 EKVFKALDQDKSGYIEKEELKRFL 68
Cdd:pfam13202   2 KDTFRQIDLNGDGKISKEELRRLL 25

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 46391079  45 EKVFKALDQDKSGYIEKEELKRFL--QNFcSKARELTEAETntlLAAGDKDGDGKIGIEEF 103
Cdd:cd16226 122 ERRWKAADQDGDGKLTKEEFTAFLhpEEF-PHMRDIVVQET---LEDIDKNKDGFISLEEY 178

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
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 46391079  47 VFKALDQDkSGYIEKEELKRFLQNFCSKAREL--TEAETNTLLAAGDKDGDGKIGIEEF 103
Cdd:cd15897   5 VFQAVAGD-DGEISATELQQALSNVGWTHFDLgfSLETCRSMIAMMDRDHSGKLNFSEF 62

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 46391079   41 SSDGEKVFKALDQDKSGYIEKEELKRFL------QNFcSKARELTEAetntLLAAGDKDGDGKIGIEEFCALL 107
Cdd:NF041410  62 LIDLSELFSDLDSDGDGSLSSDELAAAAppppppPDQ-APSTELADD----LLSALDTDGDGSISSDELSAGL 129

centrin; Provisional

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 46391079   46 KVFKALDQDKSGYIEKEELKRFLQnfcSKARELTEAETNTLLAAGDKDGDGKIGIEEF 103
Cdd:PTZ00183  21 EAFDLFDTDGSGTIDPKELKVAMR---SLGFEPKKEEIKQMIADVDKDGSGKIDFEEF 75

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 46391079  43 DGEKVFKALDQDKSGYIEKEELKRFLQNFcskARELTEAETNTLLAAGDKDGDGKIGIEEF---CALLK 108
Cdd:cd16183  68 DWQNCFRSFDRDNSGNIDKNELKQALTSF---GYRLSDQFYDILVRKFDRQGRGTIAFDDFiqcCVVLQ 133