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J. Biol. Chem., Vol. 279, Issue 9, 7917-7924, February 27, 2004

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Association of the Chaperone B-crystallin with Titin in Heart Muscle^*

Belinda Bullard, Charles Ferguson, Ave Minajeva¶, Mark C. Leake¶||, Mathias Gautel**, Dietmar Labeit, Linlin Ding, Siegfried Labeit, Joseph Horwitz, Kevin R. Leonard, and Wolfgang A. Linke¶||||

From the European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69117 Heidelberg, Germany, the ^¶Institute of Physiology and Pathophysiology, University of Heidelberg, D-69120 Heidelberg, Germany, the Institut für Anasthesiologie und Operative Intensivmedizin, Universitätsklinikum, D-68135 Mannheim, Germany, and the Jules Stein Eye Institute, UCLA, Los Angeles, California 90024

B-crystallin, a major component of the vertebrate lens, is a chaperone belonging to the family of small heat shock proteins. These proteins form oligomers that bind to partially unfolded substrates and prevent denaturation. B-crystallin in cardiac muscle binds to myofibrils under conditions of ischemia, and previous work has shown that the protein binds to titin in the I-band of cardiac fibers (Golenhofen, N., Arbeiter, A., Koob, R., and Drenckhahn, D. (2002) J. Mol. Cell. Cardiol. 34, 309–319). This part of titin extends as muscles are stretched and is made up of immunoglobulin-like modules and two extensible regions (N2B and PEVK) that have no well defined secondary structure. We have followed the position of B-crystallin in stretched cardiac fibers relative to a known part of the titin sequence. B-crystallin bound to a discrete region of the I-band that moved away from the Z-disc as sarcomeres were extended. In the physiological range of sarcomere lengths, B-crystallin bound in the position of the N2B region of titin, but not to PEVK. In overstretched myofibrils, it was also in the Ig region between N2B and the Z-disc. Binding between B-crystallin and N2B was confirmed using recombinant titin fragments. The Ig domains in an eight-domain fragment were stabilized by B-crystallin; atomic force microscopy showed that higher stretching forces were needed to unfold the domains in the presence of the chaperone. Reversible association with B-crystallin would protect I-band titin from stress liable to cause domain unfolding until conditions are favorable for refolding to the native state.

Received for publication, July 11, 2003 , and in revised form, November 10, 2003.

^* This work was supported by grants from the Deutsche Forschungsgemeinschaft (to M. G., S. L., and W. A. L.) and from the National Institutes of Health (to J. H.). 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.

^|| Present address: Clarendon Lab., University of Oxford, Parks Rd., Oxford OX1 3PU, UK.

^** Present address: Randall Centre, New Hunt's House, King's College, Guy's Campus, London SE1 1UL, UK.

^|||| Present address: Muscle Biology, University of Münster, Schlossplatz 5, D-48419, Münster, Germany.

To whom correspondence should be addressed. Tel.: 49-6221-387-268; Fax: 49-6221-387-306; E-mail: bullard{at}embl.de.

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