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J. Biol. Chem., Vol. 282, Issue 47, 34276-34287, November 23, 2007

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Myopathy-associated B-crystallin Mutants

ABNORMAL PHOSPHORYLATION, INTRACELLULAR LOCATION, AND INTERACTIONS WITH OTHER SMALL HEAT SHOCK PROTEINS^*

Stephanie Simon¹, Jean-Marc Fontaine, Jody L. Martin^¶, Xiankui Sun, Adam D. Hoppe^||, Michael J. Welsh, Rainer Benndorf, and Patrick Vicart

From the EA300 Stress et Pathologies du Cytosquelette, Université Paris 7, UFR de Biochimie, 75005 Paris, France, the Departments of Cell and Developmental Biology and ^||Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan 48109, and the ^¶Department of Medicine, Cardiovascular Institute, Loyola University Chicago, Maywood, Illinois 60153

Three mutations (R120G, Q151X, and 464delCT) in the small heat shock protein B-crystallin cause inherited myofibrillar myopathy. In an effort to elucidate the molecular basis for the associated myopathy, we have determined the following for these mutant B-crystallin proteins: (i) the formation of aggregates in transfected cells; (ii) the partition into different subcellular fractions; (iii) the phosphorylation status; and (iv) the ability to interact with themselves, with wild-typeB-crystallin, and with other small heat shock proteins that are abundant in muscles. We found that all three B-crystallin mutants have an increased tendency to form cytoplasmic aggregates in transfected cells and significantly increased levels of phosphorylation when compared with the wild-type protein. Although wild-type B-crystallin partitioned essentially into the cytosol and membranes/organelles fractions, mutant B-crystallin proteins partitioned additionally into the nuclear and cytoskeletal fractions. By using various protein interaction assays, including quantitative fluorescence resonance energy transfer measurements in live cells, we found abnormal interactions of the various B-crystallin mutants with wild-type B-crystallin, with themselves, and with the other small heat shock proteins Hsp20, Hsp22, and possibly with Hsp27. The collected data suggest that eachB-crystallin mutant has a unique pattern of abnormal interaction properties. These distinct properties of the B-crystallin mutants identified are likely to contribute to a better understanding of the gradual manifestation and clinical heterogeneity of the associated myopathy in patients.

Received for publication, April 18, 2007 , and in revised form, September 11, 2007.

^* This work was supported by the French Ministry of Research and the Association Française Contre les Myopathies (to S. S.), the CNRS, the Association Française Contre les Myopathies Grant 11764 (to P. V.), United States Public Health Service Grant P01ES11188 from the NIEHS, National Institutes of Health (to M. J. W. and R. B.), a Munn Idea grant of the University of Michigan Comprehensive Cancer Center (to R. B.), and by an American Heart Association Award (to J. L. M.). 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 Figs. 1–4 and Table 1.

¹ To whom correspondence should be addressed. Tel.: 33144274736; Fax: 33144273611; E-mail: stef.labo{at}gmail.com.

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