The EF-Hand, Homologs and Analogs

  • Robert H. Kretsinger
  • David Tolbert
  • Susumu Nakayama
  • William Pearson


Many proteins bind calcium; they have different structures and employ different coordination geometries to achieve a wide range of affinities and selectivities. Kretsinger (1975) proposed that those within the cytosol are calcium modulated, that they are in the magnesium or apoform in the quiescent cell and in the calcium form in the stimulated cell, and that they detect calcium functioning as a second messenger. Further, he proposed that these calcium modulated proteins, in contrast to the vast array of extracytosolic calcium-binding proteins, all contain the EF-hand homolog domain and are all members of one homolog family. The generality of this theory should be questioned. What exactly is a quiescent cell? How do pores and pumps figure in this scheme? Do some proteins lacking EF-hands, such as the annexins, bind messenger calcium? Do some EF-hand proteins have a high enough affinity to bind calcium in quiescent cells? Do some EF-hand proteins function in the extracytosolic environment? Do these generalizations apply to prokaryotic cells? Although we will address some of these questions, our main concern here is to identify and characterize the members of the EF-hand homolog family and to distinguish them from several very similar analogs.


Calcium Binding Query Pattern Homolog Family Canonical Domain Essential Light Chain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Au-Young J, Robbins PW (1990) Isolation of a chitin synthase gene (CHS1) from Candida albicans by expression in saccharomyces cerevisiae. Molec Microbiol 4:197–207.CrossRefGoogle Scholar
  2. Babitch JA, Anthony FA (1987) Grasping for calcium binding sites in sodium channels with an EF-hand. J Theor Biol 127:451–459.PubMedCrossRefGoogle Scholar
  3. Babu YS, Bugg CE, Cook WJ (1988) Structure of calmodulin refined at 2.2 Å resolution. J Mol Biol 204:191–204.PubMedCrossRefGoogle Scholar
  4. Bagshaw CR, Kendrick-Jones J (1980) Identification of the divalent metal for binding domain of myosin regulatory light chains using spin-labeling techniques. J Mol Biol 140:411–433.PubMedCrossRefGoogle Scholar
  5. Baker ME (1985) Evidence that progesterone binding uteroglobin is similar to myosin alkali light chain. FEBS Lett 189:188–194.PubMedCrossRefGoogle Scholar
  6. Baudier J, Glasser N, Gerard D (1986) Ions binding to S-100 proteins. I. Calcium-and Zinc-binding properties of bovine brain S-100αα, S-100a(αϟ), and S-lOOb(ϟϟ) Protein: Zn2+ regulates Ca2+ binding on S-100b protein. J Biol Chem 261:8192–8203.PubMedGoogle Scholar
  7. Beguin P, Cornet P, Aubert JP (1985) Sequence of a cellulase gene of the thermophilic bacterium Clostridium thermocellwn. J Bacteriol 162:102–105.PubMedGoogle Scholar
  8. Bolander ME, Young MF, Fisher LW, Yamada Y, Termine JD (1988) Osteonectin cDNA sequence reveals potential binding regions for calcium and hydroxyapatite and shows homologies with both a basement membrane protein (SPARC) and a serine proteinase inhibitor (Ovomucoid). Proc Natl Acad Sci 85:2919–2923.PubMedCrossRefGoogle Scholar
  9. Brandt P, Zurini M, Neve RL, Rhoads RE, Vanaman TC (1988) A C-terminal, calmodulin-like regulatory domain from the plasma membrane Ca2+-pumping ATPase. Proc Natl Acad Sci 85:2914–2918.PubMedCrossRefGoogle Scholar
  10. Bulawa CE, Slater M, Cabib E, Au-Young J, Sburlati A, Adair WL, Robbins PW (1986) The S. Cerevisiae structural gene for chitin synthase is not required for chitin synthesis in vitro. Cell 46:213–225.PubMedCrossRefGoogle Scholar
  11. Coussens L, Parker PJ, Rhee L, Yang-Feng TL, Chen E, Waterfield MD, Francke U, Ullrich A (1986) Multiple, distinct forms of bovine and human protein kinase C suggest diversity in cellular signaling pathways. Science 233:859–866.PubMedCrossRefGoogle Scholar
  12. Cox JA (1986) Isolation and characterization of a new Mr 18,000 protein with calcium vector properties in amphioxus muscle and identification of its endogenous target protein. J Biol Chem 261:13173–13178.PubMedGoogle Scholar
  13. Declercq J-P, Tinant B, Parello J, Etienne G, Huber R (1988) Crystal structure determination and refinement of pike 4.10 parvalbumin (minor component from Esox lucius). J Mol Biol 202:349–353.PubMedCrossRefGoogle Scholar
  14. Engel J, Taylor W, Paulsson M, Sage H, Hogan B (1987) Calcium binding domains and calcium-induced conformational transition of SPARC/BM-40/osteonectin, an extracellular glycoprotein expressed in mineralized and nonmineralized tissues. Biochemistry 26:6958–6965.PubMedCrossRefGoogle Scholar
  15. Fong KC, Babiteh JA, Anthony FA (1988) Calcium binding to tubulin. Biochim Biophys Acta 952:13–19.PubMedCrossRefGoogle Scholar
  16. Gonzalez A, Lerner TJ, Huecas M, Sosa-Pineda B, Nogueira N, Lizardi PM (1985) Apparent generation of a segmented mRNA from two separate tandem gene families in Trypanosoma cruzi. Nuc Acid Res 13:5789–5804.CrossRefGoogle Scholar
  17. Helman LJ, Ahn TG, Levine MA, Allison A, Cohen PS, Cooper MJ, Cohn DV, Istael MA (1988) Molecular cloning and primary structure of human chromogranin A (secretory protein I) cDNA. J Biol Chem 263:11559–11563.PubMedGoogle Scholar
  18. Herzberg O, James MNG (1988) Refined crystal structure of troponin C from turkey skeletal muscle at 2.0 Å resolution. J Mol Biol 203:761–779.PubMedCrossRefGoogle Scholar
  19. Iacangelo A, Affolter H-U, Eiden LE, Herbert E, Grimes M (1986) Bovine chromogranin A sequence and distribution of its messenger RNA in endorme tissues. Nature 323:82–86.PubMedCrossRefGoogle Scholar
  20. Inoue S, Franceschini T, Inoue M (1983) Structural similarities between the development-specific protein S from a Gram-negative bacterium, myxococcus Xanthus, and calmodulin. Proc Natl Acad Sci 80:6829–6833.CrossRefGoogle Scholar
  21. Kemple MD, Lovejoy ML, Ray BD, Prendergast FG, Rao BDN (1990) Mn (II)-EPR measurements of cation binding by aequorin. Eur J Biochem 187:131–135.PubMedCrossRefGoogle Scholar
  22. Kessler D, Eisenlohr LC, Lathwell MJ, Huang J, Taylor HC, Godfrey SD, Spady ML (1980) Physarum myosin light chain binds calcium. Cell Motility 1:63–71.PubMedCrossRefGoogle Scholar
  23. Klee CB, Crouch TH, Krinks MH (1979) Calcineurin a calcium-and calmodulin-binding protein of the nervous system. Proc Natl Acad Sci 76:6270–6273.PubMedCrossRefGoogle Scholar
  24. Kretsinger RH (1975) Hypothesis: calcium modulated proteins contain EF-hands. In: Calcium transport in contraction and secretion. E. Carafoli, F. Clementi, W. Drabikowski and A. Margreth (eds), NorthHolland Publishing Co., Amsterdam, pp 469–478.Google Scholar
  25. Kretsinger RH (1987) Calcium coordination and the calmodulin fold divergent versus convergent evolution. Cold Spring Harb Symp Quant Biol 52:499–510.PubMedGoogle Scholar
  26. Kumar VD, Lee L, Edwards BFP (1990) The refined crystal structure of calcium-liganded carp parvalbumin 4.25 at 1.5 Å resolution. Biochemistry 29:1404–1412.PubMedCrossRefGoogle Scholar
  27. Laroche A, Lemieux G, Pallotta D (1989) The nucleotide sequence of a developmentally regulated cDNA from physarum polycephalum. Nuc Acids Res 17:10502–10502.CrossRefGoogle Scholar
  28. Lawler J, Chao FC, Cohen CM (1982) Evidence for calcium-sensitive structure in platelet Thrombospondin. Isolation and partial characterization of thrombospondin in the presence of calcium. J Biol Chem 257:12257–12265.PubMedGoogle Scholar
  29. Lawyer J, Hynes RO (1986) The structure of human thrombospondin, an adhesive glycoprotein with multiple calcium-binding sites and homologies with several different proteins. J Cell Biol 103:1635–1647.CrossRefGoogle Scholar
  30. Leathers VL, Linse S, Forsén S, Norman AW (1990) Calbindin-D28k, a 1α,25-dihydroxyvitamin D3-induced calcium-binding protein, binds five or six Ca2+ ions with high affinity. J Biol Chem 265:9838–9841.PubMedGoogle Scholar
  31. Lee M G-S, Chen J, Ho AWM, D’Alesandro PA, Vander Ploeg LHT (1990) A putative flagellar Ca2+-binding protein of the flagellum of trypanosomatid protozoan parasites. Nuc Acids Res 18:4252–4252.CrossRefGoogle Scholar
  32. Moncrief ND, Goodman M, Kretsinger RH (1990) Evolution of EF-hand calcium-modulated proteins I. Relationships based on amino acid sequences. J Mol Evol 30:522–562.PubMedCrossRefGoogle Scholar
  33. Nagayoshi T, Sanborn D, Hickok NJ, Olsen DR, Fazio MJ, Chu M-L, Knowlton R, Mann K, Deutzmann R, Timpl R, Uitto J (1989) Human nidogen: complete amino acid sequence and structural domains deduced from cDNAs, and evidence for polymorphism of the gene. DNA 8:581–594.PubMedCrossRefGoogle Scholar
  34. Pallotta D, Laroche A, Tessier A, Schinnick T, Lemieux G (1986) Molecular cloning of stage specific mRNAs from amoebea. Biochem Cell Biol 64:1294–1302.CrossRefGoogle Scholar
  35. Pearson WR (1990) Rapid and sensitive sequence comparison with FASTP and FASTA. Meth Enz 183:63–98.CrossRefGoogle Scholar
  36. Poncz M, Eisman R, Heidenreich R, Silver SM, Vilaire G, Surrey S, Schwartz E, Bennett JS (1987) Structure of the platelet membrane glycoprotein IIb. Homology to the a subunits of the vitronectin and fibronectin membrane receptors. J Biol Chem 262:8476–8482.PubMedGoogle Scholar
  37. Sakane F, Yamada K, Kanon H, Yokoyama C, Tanabe T (1990) Porcine diacylglycerol kinase sequence has zinc finger and EF-hand motifs. Nature 344:345–348.PubMedCrossRefGoogle Scholar
  38. Satyshur KA, Rao ST, Pyzalska D, Drendel W, Greaser, M, Sundaralingam M (1988) Refined structure of chicken skeletal muscle troponin C in the two-calcium state at 2 Å resolution. J Biol Chem 263:1628–1647.PubMedGoogle Scholar
  39. Sharma Y, Rao ChM, Narasu ML, Rao SC, Somasundaram T, Gopalakrishna A, Balasubramanian D (1989) Calcium ion binding to δ-and to ϟ-crystallins. The presence of the “EF-hand motif” in δ-crystallin that aids in calcium ion binding. J Biol Chem 264:12794–12799.PubMedGoogle Scholar
  40. Smith TF, Waterman MS (1981) Identification of common molecular subsequences. J Mol Biol 147:195–197.PubMedCrossRefGoogle Scholar
  41. Stuart DI, Acharya KR, Walker NPC, Smith SG, Lewis M, Phillips DC (1986) α-Lactalbumin posesses a novel calcium binding loop. Nature 324:84–87.PubMedCrossRefGoogle Scholar
  42. Swain A, Amma S, Kretsinger RH (1989) Restrained least square refinement of native (calcium) and cadmiumsubstituted carp parvalbumin using X-ray crystallographic data to 1.6 υ resolution. J Biol Chem 264:16620–16628.PubMedGoogle Scholar
  43. Szebenyi DME, Moffat K (1986) The refined structure of vitamin D-dependent calcium-binding protein from bovine intestine. Molecular details, ion binding, and implications for the structure of other calciumbinding proteins. J Biol Chem 261:8761–8777.PubMedGoogle Scholar
  44. Tufty RM, Kretsinger RH (1975) Troponin and parvalbumin calcium-binding regions predicted in myosin light chain and T4 lysozyme. Science 187:167–169.PubMedCrossRefGoogle Scholar
  45. Vyas NK, Vyas MN, Quiocho FA (1987) A novel calcium-binding site in the galactose-binding protein of bacterial transport and chemotaxis. Nature 327:635–638.PubMedCrossRefGoogle Scholar
  46. Yoshimura N, Kikuchi T, Sasaki T, Kitahara A, Hatanaka M, Murachi T (1983) Two distinct Ca2+ proteins (calpain I and calpain II) purified concurrently by the same method from rat kidney. J Biol Chem 258:8883–8889.PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1991

Authors and Affiliations

  • Robert H. Kretsinger
  • David Tolbert
  • Susumu Nakayama
  • William Pearson

There are no affiliations available

Personalised recommendations