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Crystal structure of human grancalcin, a member of the penta-EF-hand protein family.

Jia J, Han Q, Borregaard N, Lollike K, Cygler M
J Mol Biol 300 1271-81 (2000)
Cited: 27 times
EuropePMC logo PMID: 10903868

Abstract

Grancalcin is a Ca(2+)-binding protein expressed at high level in neutrophils. It belongs to the PEF family, proteins containing five EF-hand motifs and which are known to associate with membranes in Ca(2+)-dependent manner. Prototypic members of this family are Ca(2+)-binding domains of calpain. Our recent finding that grancalcin interacts with L-plastin, a protein known to have actin bundling activity, suggests that grancalcin may play a role in regulation of adherence and migration of neutrophils. The structure of human grancalcin has been determined at 1.9 A resolution in the absence of calcium (R-factor of 0.212 and R-free of 0.249) and at 2. 5 A resolution in the presence of calcium (R-factor of 0.226 and R-free of 0.281). The molecule is predominantly alpha-helical: it contains eight alpha-helices and only two short stretches of two-stranded beta-sheets between the loops of paired EF-hands. Grancalcin forms dimers through the association of the unpaired EF5 hands in a manner similar to that observed in calpain, confirming this mode of association as a paradigm for the PEF family. Only one Ca(2+) was found per dimer under crystallization conditions that included CaCl(2). This cation binds to EF3 in one molecule, while this site in the second molecule of the dimer is unoccupied. This unoccupied site shows higher mobility. The structure determined in the presence of calcium, although does not represent a fully Ca(2+)-loaded form, suggests that calcium induces rather small conformational rearrangements. Comparison with calpain suggests further that the relatively small magnitude of conformational changes invoked by calcium alone may be a characteristic feature of the PEF family. Moreover, the largest differences are localized to the EF1, thus supporting the notion that calcium signaling occurs through this portion of the molecule and that it may involve the N-terminal Gly/Pro rich segment. Electrostatic potential distribution shows significant differences between grancalcin and calpain domain VI demonstrating their distinct character.

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Reviews citing this publication (1)

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Articles citing this publication (20)

  1. Mechanism of Ca2+ activation of the NADPH oxidase 5 (NOX5). Bánfi B, Tirone F, Durussel I, Knisz J, Moskwa P, Molnár GZ, Krause KH, Cox JA. J Biol Chem 279 18583-18591 (2004)
  2. Peflin and ALG-2, members of the penta-EF-hand protein family, form a heterodimer that dissociates in a Ca2+-dependent manner. Kitaura Y, Matsumoto S, Satoh H, Hitomi K, Maki M. J Biol Chem 276 14053-14058 (2001)
  3. Structural basis for Ca2+ -dependent formation of ALG-2/Alix peptide complex: Ca2+/EF3-driven arginine switch mechanism. Suzuki H, Kawasaki M, Inuzuka T, Okumura M, Kakiuchi T, Shibata H, Wakatsuki S, Maki M. Structure 16 1562-1573 (2008)
  4. Sorcin regulates excitation-contraction coupling in the heart. Meyers MB, Fischer A, Sun YJ, Lopes CM, Rohacs T, Nakamura TY, Zhou YY, Lee PC, Altschuld RA, McCune SA, Coetzee WA, Fishman GI. J Biol Chem 278 28865-28871 (2003)
  5. Biochemical characterization of the penta-EF-hand protein grancalcin and identification of L-plastin as a binding partner. Lollike K, Johnsen AH, Durussel I, Borregaard N, Cox JA. J Biol Chem 276 17762-17769 (2001)
  6. The crystal structure of the sorcin calcium binding domain provides a model of Ca2+-dependent processes in the full-length protein. Ilari A, Johnson KA, Nastopoulos V, Verzili D, Zamparelli C, Colotti G, Tsernoglou D, Chiancone E. J Mol Biol 317 447-458 (2002)
  7. Crystal structure of calcium-free human sorcin: a member of the penta-EF-hand protein family. Xie X, Dwyer MD, Swenson L, Parker MH, Botfield MC. Protein Sci 10 2419-2425 (2001)
  8. 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 JW, Cox J, Durussel I, Walker TM, van Ginkel PR, Bhattacharya S, Dellaria JM, Palczewski K, Polans AS. Biochemistry 43 11175-11186 (2004)
  9. Both ALG-2 and peflin, penta-EF-hand (PEF) proteins, are stabilized by dimerization through their fifth EF-hand regions. Kitaura Y, Satoh H, Takahashi H, Shibata H, Maki M. Arch Biochem Biophys 399 12-18 (2002)
  10. Crystal structure of calpain-3 penta-EF-hand (PEF) domain - a homodimerized PEF family member with calcium bound at the fifth EF-hand. Partha SK, Ravulapalli R, Allingham JS, Campbell RL, Davies PL. FEBS J 281 3138-3149 (2014)
  11. Molecular basis for the impaired function of the natural F112L sorcin mutant: X-ray crystal structure, calcium affinity, and interaction with annexin VII and the ryanodine receptor. Franceschini S, Ilari A, Verzili D, Zamparelli C, Antaramian A, Rueda A, Valdivia HH, Chiancone E, Colotti G. FASEB J 22 295-306 (2008)
  12. Distinguishing between calpain heterodimerization and homodimerization. Ravulapalli R, Campbell RL, Gauthier SY, Dhe-Paganon S, Davies PL. FEBS J 276 973-982 (2009)
  13. Molecular basis for defect in Alix-binding by alternatively spliced isoform of ALG-2 (ALG-2DeltaGF122) and structural roles of F122 in target recognition. Inuzuka T, Suzuki H, Kawasaki M, Shibata H, Wakatsuki S, Maki M. BMC Struct Biol 10 25 (2010)
  14. Granulocyte function in grancalcin-deficient mice. Roes J, Choi BK, Power D, Xu P, Segal AW. Mol Cell Biol 23 826-830 (2003)
  15. The PEF family proteins sorcin and grancalcin interact in vivo and in vitro. Hansen C, Tarabykina S, la Cour JM, Lollike K, Berchtold MW. FEBS Lett 545 151-154 (2003)
  16. Grancalcin (GCA) modulates Toll-like receptor 9 (TLR9) mediated signaling through its direct interaction with TLR9. Kim TW, Hong S, Talukder AH, Pascual V, Liu YJ. Eur J Immunol 46 712-724 (2016)
  17. A second binding site revealed by C-terminal truncation of calpain small subunit, a penta-EF-hand protein. Leinala EK, Arthur JS, Grochulski P, Davies PL, Elce JS, Jia Z. Proteins 53 649-655 (2003)
  18. Linkage scan of nicotine dependence in the University of California, San Francisco (UCSF) Family Alcoholism Study. Gizer IR, Ehlers CL, Vieten C, Seaton-Smith KL, Feiler HS, Lee JV, Segall SK, Gilder DA, Wilhelmsen KC. Psychol Med 41 799-808 (2011)
  19. Metal-free and Ca2+-bound structures of a multidomain EF-hand protein, CBP40, from the lower eukaryote Physarum polycephalum. Iwasaki W, Sasaki H, Nakamura A, Kohama K, Tanokura M. Structure 11 75-85 (2003)
  20. Molecular modeling, molecular dynamics simulation, and essential dynamics analysis of grancalcin: An upregulated biomarker in experimental autoimmune encephalomyelitis mice. Paul SK, Saddam M, Rahaman KA, Choi JG, Lee SS, Hasan M. Heliyon 8 e11232 (2022)


Related citations provided by authors (1)

  1. Crystallization and preliminary X-ray analysis of human grancalcin, a novel cytosolic Ca2+-binding protein present in leukocytes. Han Q, Jia J, Li Y, Lollike K, Cygler M Acta Crystallogr. D Biol. Crystallogr. 56 772-774 (2000)

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