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A more recent version of this article appeared on May 1, 2002
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Submitted on September 11, 2001
Revised on December 21, 2001
Accepted on January 28, 2002
1 Department of Physiology, University of Wisconsin Medical School, 1300 University Avenue, Madison, WI 53706, USA
2 Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK
3 Department of Pathology and Laboratory Medicine, Robert Wood
Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854
* Corresponding author. E-mail address: ervasti{at}physiology.wisc.edu.
Dystrophin is widely thought to mechanically link the cortical cytoskeleton with the muscle sarcolemma. While the dystrophin homologue utrophin can functionally compensate for dystrophin in mice, recent studies question whether utrophin can bind laterally along actin filaments and anchor filaments to the sarcolemma. Here, we have expressed full-length recombinant utrophin and show that the purified protein is fully soluble with a native molecular weight and molecular dimensions indicative of monomers. We demonstrate that like dystrophin, utrophin can form an extensive lateral association with actin filaments and protect actin filaments from depolymerization in vitro. However, utrophin binds laterally along actin filaments through contribution of acidic spectrin-like repeats rather than the cluster of basic repeats employed by dystrophin. We also show that the defective linkage between costameric actin filaments and the sarcolemma in dystrophin-deficient mdx muscle is rescued by overexpression of utrophin. Our results demonstrate that utrophin and dystrophin are functionally interchangeable actin binding proteins, but that the molecular epitopes important for filament binding differ between the two proteins. More generally, our results raise the possibility that spectrin-like repeats may enable some members of the plakin family of cytolinkers to laterally bind and stabilize actin filaments.
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