ef hand motifs


Summary: Calcium-binding motifs composed of two helices (E and F) joined by a loop. Calcium is bound by the loop region. These motifs are found in many proteins that are regulated by calcium.

Top Publications

  1. Huang X, Poy F, Zhang R, Joachimiak A, Sudol M, Eck M. Structure of a WW domain containing fragment of dystrophin in complex with beta-dystroglycan. Nat Struct Biol. 2000;7:634-8 pubmed
    ..Additionally, the structure reveals striking similarities in the mechanisms of proline recognition employed by WW domains and SH3 domains. ..
  2. Brunet S, Scheuer T, Klevit R, Catterall W. Modulation of CaV1.2 channels by Mg2+ acting at an EF-hand motif in the COOH-terminal domain. J Gen Physiol. 2005;126:311-23 pubmed
    ..2 channels, and reveal a potentially important role of Mg(i) binding to the COOH-terminal EF-hand in regulating Ca(2+) influx in physiological and pathophysiological states. ..
  3. Vernarecci S, Colotti G, Ornaghi P, Schiebel E, Chiancone E, Filetici P. The yeast penta-EF protein Pef1p is involved in cation-dependent budding and cell polarization. Mol Microbiol. 2007;65:1122-38 pubmed
    ..Our data suggest that cation homeostasis is involved in the control of polarized growth and in stress response in budding yeast. ..
  4. Grabarek Z. Structural basis for diversity of the EF-hand calcium-binding proteins. J Mol Biol. 2006;359:509-25 pubmed
  5. Santamaria Kisiel L, Rintala Dempsey A, Shaw G. Calcium-dependent and -independent interactions of the S100 protein family. Biochem J. 2006;396:201-14 pubmed
  6. Leukert N, Vogl T, Strupat K, Reichelt R, Sorg C, Roth J. Calcium-dependent tetramer formation of S100A8 and S100A9 is essential for biological activity. J Mol Biol. 2006;359:961-72 pubmed
    ..This is the first report showing a functional relevance of calcium-induced higher-order oligomerization in the S100 family. ..
  7. Ravulapalli R, Diaz B, Campbell R, Davies P. Homodimerization of calpain 3 penta-EF-hand domain. Biochem J. 2005;388:585-91 pubmed
    ..Molecular modelling suggests that there would be no barriers to the dimerization of the whole enzyme through the PEF domains. This orientation would place the catalytic centres at opposite ends of the dimer. ..
  8. Vega I, Traverso E, Ferrer Acosta Y, Matos E, Colon M, Gonzalez J, et al. A novel calcium-binding protein is associated with tau proteins in tauopathy. J Neurochem. 2008;106:96-106 pubmed publisher
  9. Stathopulos P, Zheng L, Li G, Plevin M, Ikura M. Structural and mechanistic insights into STIM1-mediated initiation of store-operated calcium entry. Cell. 2008;135:110-22 pubmed publisher
    ..We provide atomic resolution insight into the molecular basis for STIM1-mediated SOCE initiation and show that the folded/unfolded state of the Ca2+-sensing region of STIM is crucial to SOCE regulation. ..

More Information


  1. Ravasi T, Hsu K, Goyette J, Schroder K, Yang Z, Rahimi F, et al. Probing the S100 protein family through genomic and functional analysis. Genomics. 2004;84:10-22 pubmed
    ..Evolution of the S100 proteins appears to have occurred in a modular fashion, also seen in other protein families such as the C2H2-type zinc-finger family. ..
  2. Li C, Chan J, Haeseleer F, Mikoshiba K, Palczewski K, Ikura M, et al. Structural insights into Ca2+-dependent regulation of inositol 1,4,5-trisphosphate receptors by CaBP1. J Biol Chem. 2009;284:2472-81 pubmed publisher
    ..We propose that CaBP1 may regulate Ca2+-dependent activity of InsP3Rs by promoting structural contacts between the suppressor and core domains. ..
  3. Zhang S, Yu Y, Roos J, Kozak J, Deerinck T, Ellisman M, et al. STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane. Nature. 2005;437:902-5 pubmed
    ..We propose that STIM1 functions as the missing link between Ca2+ store depletion and SOC influx, serving as a Ca2+ sensor that translocates upon store depletion to the plasma membrane to activate CRAC channels. ..
  4. Day I, Reddy V, Shad Ali G, Reddy A. Analysis of EF-hand-containing proteins in Arabidopsis. Genome Biol. 2002;3:RESEARCH0056 pubmed
    ..Our analyses suggest that the Ca2+ messenger system is widely used in plants and that EF-hand-containing proteins are likely to be the key transducers mediating Ca2+ action. ..
  5. Ikura M, Osawa M, Ames J. The role of calcium-binding proteins in the control of transcription: structure to function. Bioessays. 2002;24:625-36 pubmed
    ..In light of the structural studies reported to date, this review provides an overview of the structural basis of EF-hand Ca(2+)-binding proteins linked with transcriptional regulation. ..
  6. Yang W, Lee H, Hellinga H, Yang J. Structural analysis, identification, and design of calcium-binding sites in proteins. Proteins. 2002;47:344-56 pubmed
    ..Our results suggest that it is possible to identify calcium- and magnesium-binding sites in proteins and design de novo metal-binding sites. ..
  7. Ilari A, Johnson K, Nastopoulos V, Verzili D, Zamparelli C, Colotti G, et al. The crystal structure of the sorcin calcium binding domain provides a model of Ca2+-dependent processes in the full-length protein. J Mol Biol. 2002;317:447-58 pubmed
  8. Gribenko A, Hopper J, Makhatadze G. Molecular characterization and tissue distribution of a novel member of the S100 family of EF-hand proteins. Biochemistry. 2001;40:15538-48 pubmed
    ..The highest levels were found in spleen and leukocytes. S100Z gene expression appears to be deregulated in some tumor tissues, compared to expression in their normal counterparts. ..
  9. Zheng L, Stathopulos P, Schindl R, Li G, Romanin C, Ikura M. Auto-inhibitory role of the EF-SAM domain of STIM proteins in store-operated calcium entry. Proc Natl Acad Sci U S A. 2011;108:1337-42 pubmed publisher
    ..Together, our data suggest that divergent Ca(2+)- and SAM-dependent stabilization of the EF-SAM fold contributes to the disparate regulation of store-operated Ca(2+) entry by STIM1 and STIM2. ..
  10. Gifford J, Walsh M, Vogel H. Structures and metal-ion-binding properties of the Ca2+-binding helix-loop-helix EF-hand motifs. Biochem J. 2007;405:199-221 pubmed
    ..A structural approach is used in this review to examine the diversity of family members, and a biophysical perspective provides insight into the ability of the EF-hand motif to bind Ca2+ with a wide range of affinities. ..
  11. Hagen S, Brachs S, Kroczek C, Fürnrohr B, Lang C, Mielenz D. The B cell receptor-induced calcium flux involves a calcium mediated positive feedback loop. Cell Calcium. 2012;51:411-7 pubmed publisher
    ..Hence, EFhd2 regulates the BCR-elicited calcium flux through a calcium-dependent positive feedback mechanism in WEHI231 cells. ..
  12. Braun A, Sy L. Contribution of potential EF hand motifs to the calcium-dependent gating of a mouse brain large conductance, calcium-sensitive K(+) channel. J Physiol. 2001;533:681-95 pubmed
    ..g. SDS-PAGE). 5. Our results suggest that two regions within the mammalian BK(Ca) channel alpha subunit, with sequence similarities to an EF hand motif, functionally contribute to the calcium-sensitive gating of this channel. ..
  13. Donato R. S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles. Int J Biochem Cell Biol. 2001;33:637-68 pubmed
    ..Future analyses should discriminate between functionally relevant S100 interactions with target proteins and in vitro observations devoid of physiological importance. ..
  14. Otterhag L, Sommarin M, Pical C. N-terminal EF-hand-like domain is required for phosphoinositide-specific phospholipase C activity in Arabidopsis thaliana. FEBS Lett. 2001;497:165-70 pubmed
  15. Morgan R, Martin Almedina S, Garcia M, Jhoncon Kooyip J, Fernandez M. Deciphering function and mechanism of calcium-binding proteins from their evolutionary imprints. Biochim Biophys Acta. 2006;1763:1238-49 pubmed
    ..Receptor docking models supported the hypothesis of a potential interaction between annexin and C2 domains as a propitious mechanism for ensuring membrane translocation during signal transduction. ..
  16. Zhou Y, Yang W, Kirberger M, Lee H, Ayalasomayajula G, Yang J. Prediction of EF-hand calcium-binding proteins and analysis of bacterial EF-hand proteins. Proteins. 2006;65:643-55 pubmed
  17. Lee L, Chen K, Chang L. Functional roles of EF-hands in human potassium channel-interacting protein 2.2. Protein Pept Lett. 2009;16:1081-7 pubmed
    ..2, our data show that the intact EF-hands should be crucial for the formation of active conformation of KChIP2.2 when the protein is loaded with Ca(2+) and Mg(2+). ..
  18. Baehr W, Palczewski K. Guanylate cyclase-activating proteins and retina disease. Subcell Biochem. 2007;45:71-91 pubmed
    ..This report provides a recent account of the advances, challenges, and possible future prospects of studying this important step in visual transduction that transcends to other neuronal Ca2+ homeostasis processes. ..
  19. Suzuki H, Kawasaki M, Inuzuka T, Okumura M, Kakiuchi T, Shibata H, et al. Structural basis for Ca2+ -dependent formation of ALG-2/Alix peptide complex: Ca2+/EF3-driven arginine switch mechanism. Structure. 2008;16:1562-73 pubmed publisher
    ..Based on these results, together with the results of in vitro binding assay with mutant ALG-2 and Alix proteins, we propose a Ca(2+)/EF3-driven arginine switch mechanism for ALG-2 binding to Alix. ..
  20. Chen N, Ye Y, Zou J, Li S, Wang S, Martin A, et al. Fluorescence complementation via EF-hand interactions. J Biotechnol. 2009;142:205-13 pubmed publisher
    ..This novel application of calcium-dependent fluorescence complementation has the potential to monitor protein-protein interactions triggered by calcium signalling pathways in living cells. ..
  21. Jain G, Pendola M, Huang Y, Juan Colas J, Gebauer D, Johnson S, et al. Functional Prioritization and Hydrogel Regulation Phenomena Created by a Combinatorial Pearl-Associated Two-Protein Biomineralization Model System. Biochemistry. 2017;56:3607-3618 pubmed publisher
    ..Thus, the pearl-associated PFMG1 and PFMG2 proteins interact and exhibit mineralization functionalities in specific ways, which may be relevant for pearl formation. ..
  22. Hoh F, Cavé A, Strub M, Baneres J, Padilla A. Removing the invariant salt bridge of parvalbumin increases flexibility in the AB-loop structure. Acta Crystallogr D Biol Crystallogr. 2009;65:733-43 pubmed publisher
    ..Normal-mode analysis indeed indicated an altered orientation of the AB domain with regard to the CD-EF binding domains. ..
  23. He H, Li J, Weng S, Li M, Yu Y. S100A11: diverse function and pathology corresponding to different target proteins. Cell Biochem Biophys. 2009;55:117-26 pubmed publisher
    ..We intend to illustrate the biological function of the S100 protein, and shed light on the further research, which will provide us with a better understanding of it. ..
  24. Tsai W, Lin Y, Tsai S, Shen W, Chao T, Lee S, et al. Lack of modulatory function of coding nucleotide polymorphism S100A2_185G>A in oral squamous cell carcinoma. Oral Dis. 2011;17:283-90 pubmed publisher
    ..Moreover, no minor S100A2_185A allele was detected in 54-pairwise clinical specimens. The coding sequence polymorphism S100A2_185G>A had no regulatory role in S100A2-mediated tumor suppression in oral cancer. ..
  25. Senawong G, Laha T, Loukas A, Brindley P, Sripa B. Cloning, expression, and characterization of a novel Opisthorchis viverrini calcium-binding EF-hand protein. Parasitol Int. 2012;61:94-100 pubmed publisher
    ..Moreover, rOv CaBP protein showed a calcium-binding property in non-denaturing gel mobility shift assay...
  26. Orr R, Kinkead R, Newman R, Anderson L, Hoey E, Trudgett A, et al. FhCaBP4: a Fasciola hepatica calcium-binding protein with EF-hand and dynein light chain domains. Parasitol Res. 2012;111:1707-13 pubmed
    ..The molecular model reveals that the calcium ion-binding site is located close to a key sequence in the DLC-like domain, suggesting a plausible mechanism for calcium-dependent dimerisation...
  27. Lorenz S, Aust G, Krohn K. Ca(2+)-binding protein expression in primary human thyrocytes. Biochim Biophys Acta. 2013;1833:2703-2713 pubmed publisher
    ..This represents a novel putative cross-regulating mechanism in thyrocytes that could affect thyrocyte signaling and physiology. ..
  28. Thépaut M, Strub M, Cave A, Baneres J, Berchtold M, Dumas C, et al. Structure of rat parvalbumin with deleted AB domain: implications for the evolution of EF hand calcium-binding proteins and possible physiological relevance. Proteins. 2001;45:117-28 pubmed
    ..The AB domain of PV protects the hydrophobic core, and is required to maintain high affinity for divalent cation binding. Therefore, the AB domain possibly modulates PV buffer function. ..
  29. Schubert W, G bel G, Diepholz M, Darji A, Kloer D, Hain T, et al. Internalins from the human pathogen Listeria monocytogenes combine three distinct folds into a contiguous internalin domain. J Mol Biol. 2001;312:783-94 pubmed publisher
  30. Ames J, Hamasaki N, Molchanova T. Structure and calcium-binding studies of a recoverin mutant (E85Q) in an allosteric intermediate state. Biochemistry. 2002;41:5776-87 pubmed
    ..We propose that Ca2+-bound myr-E85Q may represent a stable intermediate state in the kinetic mechanism of the calcium-myristoyl switch. ..
  31. Sathyanarayanan P, Poovaiah B. Decoding Ca2+ signals in plants. CRC Crit Rev Plant Sci. 2004;23:1-11 pubmed
    ..This review summarizes the elements of conformational coupling and molecular mechanisms of regulation of the two groups of protein kinases by Ca2+ and Ca2+/calmodulin in plants. ..
  32. Fanani M, Topham M, Walsh J, Epand R. Lipid modulation of the activity of diacylglycerol kinase alpha- and zeta-isoforms: activation by phosphatidylethanolamine and cholesterol. Biochemistry. 2004;43:14767-77 pubmed
    ..However, a truncated form lacking only the recoverin homology domain is partially activated by either calcium or certain lipids. ..
  33. de Alba E, Tjandra N. Structural studies on the Ca2+-binding domain of human nucleobindin (calnuc). Biochemistry. 2004;43:10039-49 pubmed
    ..NMR relaxation data and structural studies of the folded domain indicate that it undergoes slow dynamics, suggesting that it is floppier and less compact than a globular domain. ..
  34. Wingo T, Shah V, Anderson M, Lybrand T, Chazin W, Balser J. An EF-hand in the sodium channel couples intracellular calcium to cardiac excitability. Nat Struct Mol Biol. 2004;11:219-25 pubmed
    ..These studies reveal the molecular basis for certain forms of long QT syndrome and other arrhythmia-producing syndromes, and suggest a potential pharmacological target for antiarrhythmic drug design. ..
  35. Maki M, Kitaura Y, Satoh H, Ohkouchi S, Shibata H. Structures, functions and molecular evolution of the penta-EF-hand Ca2+-binding proteins. Biochim Biophys Acta. 2002;1600:51-60 pubmed
    ..The Group I genes have also been found in lower animals, plants, fungi and protists. Recent findings of specific interacting proteins have started to gradually unveil the functions of the noncatalytic mammalian PEF proteins. ..
  36. Tommasi di Vignano A, Di Zenzo G, Sudol M, Cesareni G, Dente L. Contribution of the different modules in the utrophin carboxy-terminal region to the formation and regulation of the DAP complex. FEBS Lett. 2000;471:229-34 pubmed
    ..The remaining two motifs found in the carboxy-terminus (H1-H2) mediate the formation of utrophin-dystrobrevin hybrids but do not select ligands in a repertoire of random nonapeptides. ..
  37. Webb K, Sk t L, Nicholson M, J rgensen B, Mizen S. Mesorhizobium loti increases root-specific expression of a calcium-binding protein homologue identified by promoter tagging in Lotus japonicus. Mol Plant Microbe Interact. 2000;13:606-16 pubmed publisher
    ..japonicus. Expression was reduced in roots inoculated with non-nodulating M. loti mutants and in progeny homozygous for the T-DNA insertion, suggesting a link between the T-DNA insertion and this gene...
  38. Chung E, Kim T, Hong S, Yong T. An EF-handed Ca(2+)-binding protein of Chinese liver fluke Clonorchis sinensis. Parasitol Res. 2013;112:4121-8 pubmed publisher
    ..CsCa8 was localized in oral and ventral suckers, vitelline follicles and subtegumental tissues. These findings suggest that CsCa8 might be involved in cellular Ca(2+) signal transduction for muscle contraction and egg production. ..
  39. Subpipattana P, Grams R, Vichasri Grams S. Analysis of a calcium-binding EF-hand protein family in Fasciola gigantica. Exp Parasitol. 2012;130:364-73 pubmed publisher
  40. Kapur M, Wang W, Maloney M, Millan I, Lundin V, Tran T, et al. Calcium tips the balance: a microtubule plus end to lattice binding switch operates in the carboxyl terminus of BPAG1n4. EMBO Rep. 2012;13:1021-9 pubmed publisher
    ..This switch is EF-hand dependent, and mutations of the EF-hands abolish this dynamic behaviour. Our study thus uncovers a new, calcium-dependent regulatory mechanism for a spectraplakin, BPAG1n4, at the MT plus end. ..
  41. Pujades C, Alon R, Yauch R, Masumoto A, Burkly L, Chen C, et al. Defining extracellular integrin alpha-chain sites that affect cell adhesion and adhesion strengthening without altering soluble ligand binding. Mol Biol Cell. 1997;8:2647-57 pubmed
    ..Thus, mutation of integrin alpha4 "EF-hand-like" sites may impair 1) static cell adhesion and 2) adhesion strengthening under shear flow by a mechanism that does not involve alterations of initial ligand binding. ..
  42. Guo W, Sun B, Xiao Z, Liu Y, Wang Y, Zhang L, et al. The EF-hand Ca2+ Binding Domain Is Not Required for Cytosolic Ca2+ Activation of the Cardiac Ryanodine Receptor. J Biol Chem. 2016;291:2150-60 pubmed publisher
    ..These results indicate that, although the EF-hand domain is not required for RyR2 activation by cytosolic Ca(2+), it plays an important role in luminal Ca(2+) activation and SOICR. ..
  43. Chung H, Ko D, Moon H, Jeong B. EF-Hand Mimicking Calcium Binding Polymer. Biomacromolecules. 2016;17:1075-82 pubmed publisher
    ..The CBP has selectivity for Ca(2+), and binding affinity for Ca(2+) was similar to the biological Ca(2+) binding motif of calmodulin. ..
  44. Peshenko I, Dizhoor A. Ca2+ and Mg2+ binding properties of GCAP-1. Evidence that Mg2+-bound form is the physiological activator of photoreceptor guanylyl cyclase. J Biol Chem. 2006;281:23830-41 pubmed
    ..Our results demonstrate that Mg2+ regulates GCAP-1 not only by adjusting its Ca2+ sensitivity to the physiological conditions in photoreceptors but also by creating the conformation required for RetGC stimulation. ..
  45. Huang Y, Wang K. The calpain family and human disease. Trends Mol Med. 2001;7:355-62 pubmed
    ..This review describes our current understanding of the calpain family members and their mechanistic linkages to the aforementioned diseases as well as other emerging pathological conditions. ..
  46. Satoh H, Nakano Y, Shibata H, Maki M. The penta-EF-hand domain of ALG-2 interacts with amino-terminal domains of both annexin VII and annexin XI in a Ca2+-dependent manner. Biochim Biophys Acta. 2002;1600:61-7 pubmed
    ..Two binding sites were predicted in both Anx7N and Anx11N, and the dissociation constants (K(d)) were estimated to be approximately 40-60 nM for the high-affinity site and 500-700 nM for the low-affinity site. ..
  47. Bertini I, Das Gupta S, Hu X, Karavelas T, Luchinat C, Parigi G, et al. Solution structure and dynamics of S100A5 in the apo and Ca2+-bound states. J Biol Inorg Chem. 2009;14:1097-107 pubmed publisher
  48. Venters R, Benson L, Craig T, Bagu J, Paul K, Kordys D, et al. The effects of Ca(2+) binding on the conformation of calbindin D(28K): a nuclear magnetic resonance and microelectrospray mass spectrometry study. Anal Biochem. 2003;317:59-66 pubmed
    ..EF-hands 1, 3, 4, and 5 take up Ca(2+), whereas EF-hands 2 and 6 do not. Our results support the opinion that calbindin D(28K) has characteristics of both a calcium sensor and a buffer. ..
  49. Levy J, Brès C, Geurts R, Chalhoub B, Kulikova O, Duc G, et al. A putative Ca2+ and calmodulin-dependent protein kinase required for bacterial and fungal symbioses. Science. 2004;303:1361-4 pubmed
    ..This indicates that calcium spiking is likely an essential component of the signaling cascade leading to nodule development and mycorrhizal infection, and sheds light on the biological role of plant CCaMKs. ..
  50. Tarabykina S, Mollerup J, Winding P, Berchtold M. ALG-2, a multifunctional calcium binding protein?. Front Biosci. 2004;9:1817-32 pubmed
    ..Special focus is given to controversial data on expression and localization of ALG-2, which is mainly caused by the use of ALG-2 antibodies with different specificities. ..
  51. Sheehan J, Bunick C, Hu H, Fagan P, Meyn S, Chazin W. Structure of the N-terminal calcium sensor domain of centrin reveals the biochemical basis for domain-specific function. J Biol Chem. 2006;281:2876-81 pubmed
  52. Babini E, Bertini I, Capozzi F, Chirivino E, Luchinat C. A structural and dynamic characterization of the EF-hand protein CLSP. Structure. 2006;14:1029-38 pubmed
    ..By using NMR, ITC, and ESI-MS, the calcium and magnesium binding properties were investigated. Finally, CLSP is framed into the evolutionary scheme of the calmodulin-like family. ..
  53. Lakowski T, Lee G, Okon M, Reid R, McIntosh L. Calcium-induced folding of a fragment of calmodulin composed of EF-hands 2 and 3. Protein Sci. 2007;16:1119-32 pubmed
    ..This nonnative hydrophobic core packing may contribute to the weak Ca(2+) affinity exhibited by EF-2 in the context of CaM2/3. ..