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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
MeSH Review

EF Hand Motifs

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Disease relevance of EF Hand Motifs


Psychiatry related information on EF Hand Motifs

  • S100A12 is a member of the S100 subfamily of EF-hand calcium-binding proteins; it has been shown to be one of the ligands of the 'receptor for advanced glycation end products' (RAGE) that belongs to the immunoglobulin superfamily and is involved in diabetes, Alzheimer's disease, inflammation and tumour invasion [6].

High impact information on EF Hand Motifs

  • Here, we describe a new gene in this region, EFHC1, which encodes a protein with an EF-hand motif [7].
  • Conservation of the Ca(2+) binding residues defines an ancestral general mechanism of activation for most calpain isoforms, including some that lack EF-hand domains [8].
  • A novel Ca2+ binding beta hairpin loop better resembles integrin sequence motifs than the EF hand [9].
  • The protein encoded by SLC25A13, named citrin, is bipartite in structure, containing a mitochondrial carrier motif and four EF-hand domains, suggesting it is a calcium-dependent mitochondrial solute transporter with a role in urea cycle function [10].
  • Recoverin, a recently discovered member of the EF hand superfamily, serves as a calcium sensor in vision [11].

Chemical compound and disease context of EF Hand Motifs

  • The single Ca(II) site of the Escherichia coli receptor for D-galactose and D-glucose (GGR) is structurally related to the eukaryotic EF-hand Ca(II) sites and is ideally suited as a model for understanding the structural and electrostatic basis of Ca(II) specificity [12].
  • Molecular characterization, expression in Escherichia coli, and epitope analysis of a two EF-hand calcium-binding birch pollen allergen, Bet v 4 [13].

Biological context of EF Hand Motifs

  • The P47 protein contains a potential Ca2+-binding 'EF-hand' structure and a region that strongly resembles known PKC phosphorylation sites [14].
  • We have identified three amino acid sequences, the presence of which is important for Ca2+-dependent inactivation: (i) a putative Ca2+-binding EF-hand motif, (ii) two hydrophilic residues (asparagine and glutamic acid) 77-78 amino acids downstream of the EF-hand motif, and (iii) a putative IQ calmodulin binding motif [15].
  • The aggregation and membrane fusion properties of annexin II are modulated by the association with a regulatory light chain called p11.p11 is a member of the S100 EF-hand protein family, which is unique in having lost its calcium-binding properties [16].
  • Remarkably, although NCS-1 and its non-mammalian homologue, frequenin, are members of a highly conserved EF-hand Ca(2+) binding protein family, our data show that IL1RAPL interacts only with NCS-1 through its specific C-terminal domain [17].
  • Accommodation of the Ca2+ ions into the loops of the EF-hands is seen to propagate into the active site of the protein now occupied by the coelenteramide where there is a significant repositioning and flipping of the His-175 imidazole ring as crucially required in the trigger hypothesis [18].

Anatomical context of EF Hand Motifs


Associations of EF Hand Motifs with chemical compounds

  • The four EF hands of the protein are arranged in a compact array that contrasts with the dumbbell shape of calmodulin and troponin C. A calcium ion is bound to EF hand 3, while EF hand 2 can bind samarium but not calcium in this crystal form [11].
  • However, an alternative pathway may involve members of the CalDAG-GEF/RasGRP protein family, which have structural features (calcium-binding EF hands and DAG-binding C1 domains) that suggest they can function in calcium and DAG signal integration [24].
  • A consensus Ca(2+)-binding motif (an EF hand), located on the alpha 1C subunit, was required for Ca2+ inactivation [25].
  • Here we report the first three-dimensional structure of a representative of the 2 EF-hand allergen family, Phl p 7, in the calcium-bound form [26].
  • Cab45 is ubiquitously expressed, contains an NH2-terminal signal sequence but no membrane-anchor sequences, and binds Ca2+ due to the presence of six EF-hand motifs [27].

Gene context of EF Hand Motifs

  • Although its carboxyl-terminal domain is related to serine-threonine phosphatase 2C, the ABI1 protein has a unique amino-terminal extension containing an EF hand calcium-binding site [28].
  • The Caenorhabditis elegans tra-3 gene promotes female development in XX hermaphrodites and encodes an atypical calpain regulatory protease lacking calcium-binding EF hands [29].
  • At its COOH terminus, mACF7 contains two putative EF-hand calcium-binding motifs and a segment homologous to the growth arrest-specific protein, Gas2 [30].
  • KCO1 has four putative transmembrane segments and tandem calcium-binding EF-hand motifs [31].
  • Mutants in the EF hand and cytoplasmic C terminus of STIM1 alter operational parameters of CRAC channels, including pharmacological profile and inactivation properties [32].

Analytical, diagnostic and therapeutic context of EF Hand Motifs

  • We show how Ile1654 in the CaM binding IQ motif of alpha(1C) forms the link between the Ca(2+) sensor and the downstream inactivation machinery, using the alpha(1C) EF hand motif as a signal transducer to activate the putative pore-occluder, the alpha(1C) I-II intracellular linker [33].
  • The timothy grass pollen allergen Phl p 7 assembles most of the IgE epitopes of a novel family of 2 EF-hand calcium-binding proteins and therefore represents a diagnostic marker allergen and vaccine candidate for immunotherapy [26].
  • Sequence analysis identifies six EF-hand calcium-binding domains and reveals 42% and 37% homology to chicken calretinin and calbindin D-28k, respectively [34].
  • Molecular cloning of human and mouse GCAP cDNA revealed that the known mammalian GCAPs are more than 90% similar, consist of 201-205 amino acids, and contain three identically conserved EF hand Ca2+ binding sites [35].
  • Lack of EF-hand caused reductions in the testis weight and sperm count by 30 and 60%, respectively [36].


  1. Engineering a terbium-binding site into an integral membrane protein for luminescence energy transfer. Vázquez-Ibar, J.L., Weinglass, A.B., Kaback, H.R. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  2. Methionine aminopeptidase 2 is a new target for the metastasis-associated protein, S100A4. Endo, H., Takenaga, K., Kanno, T., Satoh, H., Mori, S. J. Biol. Chem. (2002) [Pubmed]
  3. Ca2+ binding to EF hands 1 and 3 is essential for the interaction of apoptosis-linked gene-2 with Alix/AIP1 in ocular melanoma. Subramanian, L., Crabb, J.W., Cox, J., Durussel, I., Walker, T.M., van Ginkel, P.R., Bhattacharya, S., Dellaria, J.M., Palczewski, K., Polans, A.S. Biochemistry (2004) [Pubmed]
  4. Contribution of the different modules in the utrophin carboxy-terminal region to the formation and regulation of the DAP complex. Tommasi di Vignano, A., Di Zenzo, G., Sudol, M., Cesareni, G., Dente, L. FEBS Lett. (2000) [Pubmed]
  5. Chromosome 1 open reading frame 10 (C1orf10) gene is frequently down-regulated and inhibits cell proliferation in oral squamous cell carcinoma. Imai, F.L., Uzawa, K., Nimura, Y., Moriya, T., Imai, M.A., Shiiba, M., Bukawa, H., Yokoe, H., Tanzawa, H. Int. J. Biochem. Cell Biol. (2005) [Pubmed]
  6. The structure of S100A12 in a hexameric form and its proposed role in receptor signalling. Moroz, O.V., Antson, A.A., Dodson, E.J., Burrell, H.J., Grist, S.J., Lloyd, R.M., Maitland, N.J., Dodson, G.G., Wilson, K.S., Lukanidin, E., Bronstein, I.B. Acta Crystallogr. D Biol. Crystallogr. (2002) [Pubmed]
  7. Mutations in EFHC1 cause juvenile myoclonic epilepsy. Suzuki, T., Delgado-Escueta, A.V., Aguan, K., Alonso, M.E., Shi, J., Hara, Y., Nishida, M., Numata, T., Medina, M.T., Takeuchi, T., Morita, R., Bai, D., Ganesh, S., Sugimoto, Y., Inazawa, J., Bailey, J.N., Ochoa, A., Jara-Prado, A., Rasmussen, A., Ramos-Peek, J., Cordova, S., Rubio-Donnadieu, F., Inoue, Y., Osawa, M., Kaneko, S., Oguni, H., Mori, Y., Yamakawa, K. Nat. Genet. (2004) [Pubmed]
  8. A Ca(2+) switch aligns the active site of calpain. Moldoveanu, T., Hosfield, C.M., Lim, D., Elce, J.S., Jia, Z., Davies, P.L. Cell (2002) [Pubmed]
  9. A novel Ca2+ binding beta hairpin loop better resembles integrin sequence motifs than the EF hand. Springer, T.A., Jing, H., Takagi, J. Cell (2000) [Pubmed]
  10. The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein. Kobayashi, K., Sinasac, D.S., Iijima, M., Boright, A.P., Begum, L., Lee, J.R., Yasuda, T., Ikeda, S., Hirano, R., Terazono, H., Crackower, M.A., Kondo, I., Tsui, L.C., Scherer, S.W., Saheki, T. Nat. Genet. (1999) [Pubmed]
  11. Three-dimensional structure of recoverin, a calcium sensor in vision. Flaherty, K.M., Zozulya, S., Stryer, L., McKay, D.B. Cell (1993) [Pubmed]
  12. Calcium(II) site specificity: effect of size and charge on metal ion binding to an EF-hand-like site. Snyder, E.E., Buoscio, B.W., Falke, J.J. Biochemistry (1990) [Pubmed]
  13. Molecular characterization, expression in Escherichia coli, and epitope analysis of a two EF-hand calcium-binding birch pollen allergen, Bet v 4. Twardosz, A., Hayek, B., Seiberler, S., Vangelista, L., Elfman, L., Grönlund, H., Kraft, D., Valenta, R. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  14. Molecular cloning and expression of the major protein kinase C substrate of platelets. Tyers, M., Rachubinski, R.A., Stewart, M.I., Varrichio, A.M., Shorr, R.G., Haslam, R.J., Harley, C.B. Nature (1988) [Pubmed]
  15. Ca2+-sensitive inactivation of L-type Ca2+ channels depends on multiple cytoplasmic amino acid sequences of the alpha1C subunit. Zühlke, R.D., Reuter, H. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  16. The crystal structure of a complex of p11 with the annexin II N-terminal peptide. Réty, S., Sopkova, J., Renouard, M., Osterloh, D., Gerke, V., Tabaries, S., Russo-Marie, F., Lewit-Bentley, A. Nat. Struct. Biol. (1999) [Pubmed]
  17. IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis. Bahi, N., Friocourt, G., Carrié, A., Graham, M.E., Weiss, J.L., Chafey, P., Fauchereau, F., Burgoyne, R.D., Chelly, J. Hum. Mol. Genet. (2003) [Pubmed]
  18. Crystal structure of a Ca2+-discharged photoprotein: implications for mechanisms of the calcium trigger and bioluminescence. Deng, L., Markova, S.V., Vysotski, E.S., Liu, Z.J., Lee, J., Rose, J., Wang, B.C. J. Biol. Chem. (2004) [Pubmed]
  19. Traffic of Kv4 K+ channels mediated by KChIP1 is via a novel post-ER vesicular pathway. Hasdemir, B., Fitzgerald, D.J., Prior, I.A., Tepikin, A.V., Burgoyne, R.D. J. Cell Biol. (2005) [Pubmed]
  20. Recoverin, a photoreceptor-specific calcium-binding protein, is expressed by the tumor of a patient with cancer-associated retinopathy. Polans, A.S., Witkowska, D., Haley, T.L., Amundson, D., Baizer, L., Adamus, G. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  21. Ca(2+)-dependent conformational changes in guanylyl cyclase-activating protein 2 (GCAP-2) revealed by site-specific phosphorylation and partial proteolysis. Peshenko, I.V., Olshevskaya, E.V., Dizhoor, A.M. J. Biol. Chem. (2004) [Pubmed]
  22. Cloning and expression of the human S100 beta gene. Allore, R.J., Friend, W.C., O'Hanlon, D., Neilson, K.M., Baumal, R., Dunn, R.J., Marks, A. J. Biol. Chem. (1990) [Pubmed]
  23. Specific interaction of SPARC with endothelial cells is mediated through a carboxyl-terminal sequence containing a calcium-binding EF hand. Yost, J.C., Sage, E.H. J. Biol. Chem. (1993) [Pubmed]
  24. CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formation. Crittenden, J.R., Bergmeier, W., Zhang, Y., Piffath, C.L., Liang, Y., Wagner, D.D., Housman, D.E., Graybiel, A.M. Nat. Med. (2004) [Pubmed]
  25. Essential Ca(2+)-binding motif for Ca(2+)-sensitive inactivation of L-type Ca2+ channels. de Leon, M., Wang, Y., Jones, L., Perez-Reyes, E., Wei, X., Soong, T.W., Snutch, T.P., Yue, D.T. Science (1995) [Pubmed]
  26. The cross-reactive calcium-binding pollen allergen, Phl p 7, reveals a novel dimer assembly. Verdino, P., Westritschnig, K., Valenta, R., Keller, W. EMBO J. (2002) [Pubmed]
  27. Cab45, a novel (Ca2+)-binding protein localized to the Golgi lumen. Scherer, P.E., Lederkremer, G.Z., Williams, S., Fogliano, M., Baldini, G., Lodish, H.F. J. Cell Biol. (1996) [Pubmed]
  28. Arabidopsis ABA response gene ABI1: features of a calcium-modulated protein phosphatase. Leung, J., Bouvier-Durand, M., Morris, P.C., Guerrier, D., Chefdor, F., Giraudat, J. Science (1994) [Pubmed]
  29. Proteolysis in Caenorhabditis elegans sex determination: cleavage of TRA-2A by TRA-3. Sokol, S.B., Kuwabara, P.E. Genes Dev. (2000) [Pubmed]
  30. Microtubule actin cross-linking factor (MACF): a hybrid of dystonin and dystrophin that can interact with the actin and microtubule cytoskeletons. Leung, C.L., Sun, D., Zheng, M., Knowles, D.R., Liem, R.K. J. Cell Biol. (1999) [Pubmed]
  31. New structure and function in plant K+ channels: KCO1, an outward rectifier with a steep Ca2+ dependency. Czempinski, K., Zimmermann, S., Ehrhardt, T., Müller-Röber, B. EMBO J. (1997) [Pubmed]
  32. STIM1 has a plasma membrane role in the activation of store-operated Ca(2+) channels. Spassova, M.A., Soboloff, J., He, L.P., Xu, W., Dziadek, M.A., Gill, D.L. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  33. Identification of the components controlling inactivation of voltage-gated Ca2+ channels. Kim, J., Ghosh, S., Nunziato, D.A., Pitt, G.S. Neuron (2004) [Pubmed]
  34. An invertebrate calcium-binding protein of the calbindin subfamily: protein structure, genomic organization, and expression pattern of the calbindin-32 gene of Drosophila. Reifegerste, R., Grimm, S., Albert, S., Lipski, N., Heimbeck, G., Hofbauer, A., Pflugfelder, G.O., Quack, D., Reichmuth, C., Schug, B. J. Neurosci. (1993) [Pubmed]
  35. Molecular characterization of human and mouse photoreceptor guanylate cyclase-activating protein (GCAP) and chromosomal localization of the human gene. Subbaraya, I., Ruiz, C.C., Helekar, B.S., Zhao, X., Gorczyca, W.A., Pettenati, M.J., Rao, P.N., Palczewski, K., Baehr, W. J. Biol. Chem. (1994) [Pubmed]
  36. A targeted mutation of Nkd1 impairs mouse spermatogenesis. Li, Q., Ishikawa, T.O., Miyoshi, H., Oshima, M., Taketo, M.M. J. Biol. Chem. (2005) [Pubmed]
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