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J. Biol. Chem., Vol. 283, Issue 8, 5046-5057, February 22, 2008

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S100A1 Binds to the Calmodulin-binding Site of Ryanodine Receptor and Modulates Skeletal Muscle Excitation-Contraction Coupling^*

Benjamin L. Prosser¹², Nathan T. Wright¹²³, Erick O. Hernãndez-Ochoa, Kristen M. Varney, Yewei Liu, Rotimi O. Olojo, Danna B. Zimmer, David J. Weber⁴, and Martin F. Schneider⁵

From the Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201 and the Department of Veterinary Pathobiology, College of Veterinary Medicine, Texas A&M University, College Station, Texas 77843-44467

S100A1, a 21-kDa dimeric Ca²⁺-binding protein, is an enhancer of cardiac Ca²⁺ release and contractility and a potential therapeutic agent for the treatment of cardiomyopathy. The role of S100A1 in skeletal muscle has been less well defined. Additionally, the precise molecular mechanism underlying S100A1 modulation of sarcoplasmic reticulum Ca²⁺ release in striated muscle has not been fully elucidated. Here, utilizing a genetic approach to knock out S100A1, we demonstrate a direct physiological role of S100A1 in excitation-contraction coupling in skeletal muscle. We show that the absence of S100A1 leads to decreased global myoplasmic Ca²⁺ transients following electrical excitation. Using high speed confocal microscopy, we demonstrate with high temporal resolution depressed activation of sarcoplasmic reticulum Ca²⁺ release in S100A1^-/- muscle fibers. Through competition assays with sarcoplasmic reticulum vesicles and through tryptophan fluorescence experiments, we also identify a novel S100A1-binding site on the cytoplasmic face of the intact ryanodine receptor that is conserved throughout striated muscle and corresponds to a previously identified calmodulin-binding site. Using a 12-mer peptide of this putative binding domain, we demonstrate low micromolar binding affinity to S100A1. NMR spectroscopy reveals this peptide binds within the Ca²⁺-dependent hydrophobic pocket of S100A1. Taken together, these data suggest that S100A1 plays a significant role in skeletal muscle excitation-contraction coupling, primarily through specific interactions with a conserved binding domain of the ryanodine receptor. This warrants further investigation into the use of S100A1 as a therapeutic target for the treatment of both cardiac and skeletal myopathies.

Received for publication, November 9, 2007 , and in revised form, December 11, 2007.

^* This work was supported by National Institutes of Health NIAMS Research Grant RO1 AR055099 (to M. F. S.) and National Institutes of Health Grants GM58888 and CA107331 (to D. J. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1 and Fig. 1.

¹ Both authors contributed equally to this work.

² Supported in part by National Institutes of Health NIAMS Training Grant T32 AR007592 to the Interdisciplinary Program in Muscle Biology, University of Maryland School of Medicine.

³ Supported in part by American Heart Association Training Grant 0615343U.

⁴ To whom correspondence may be addressed. Tel.: 410-706-4354; Fax: 410-706-0458; E-mail: dweber{at}umaryland.edu.

⁵ To whom correspondence may be addressed: 108 N. Greene St., Baltimore, MD 21201. Tel.: 410-706-7812; E-mail: mschneid{at}umaryland.edu.

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