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J. Biol. Chem., Vol. 279, Issue 16, 16410-16416, April 16, 2004

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Influence of Lateral Association on Forced Unfolding of Antiparallel Spectrin Heterodimers^*

Richard Law, Sandy Harper, David W. Speicher, and Dennis E. Discher¶

From the Department of Chemical and Biomolecular Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6315 and the Structural Biology Program, The Wistar Institute, Philadelphia, Pennsylvania 19104

Protein extensibility appears to be based broadly on conformational changes that can in principle be modulated by protein-protein interactions. Spectrin family proteins, with their extensible three-helix folds, enable evaluation of dimerization effects at the single molecule level by atomic force microscopy. Although some spectrin family members function physiologically only as homodimers (e.g. -actinin) or are strictly monomers (e.g. dystrophin), - and -spectrins are stable as monomeric forms but occur physiologically as ,-heterodimers bound laterally lengthwise. For short constructs of - and -spectrin, either as monomers or as ,-dimers, sawtooth patterns in atomic force microscopy-forced extension show that unfolding stochastically extends repeats 4–5-fold greater in length than native conformations. For both dimers and monomers, distributions of unfolding lengths appear bimodal; major unfolding peaks reflect single repeats, and minor unfolding peaks at twice the length reflect tandem repeats. Cooperative unfolding thus propagates through helical linkers between serial repeats (1, 2). With lateral heterodimers, however, the force distribution is broad and shifted to higher forces. The associated chains in a dimer can stay together and unfold simultaneously in addition to unfolding independently. Weak lateral interactions do not inhibit unfolding, but strong lateral interactions facilitate simultaneous unfolding analogous to serial repeat coupling within spectrin family proteins.

Received for publication, December 2, 2003 , and in revised form, January 22, 2004.

^* This work was supported by grants from the National Institutes of Health, National Science Foundation, and the Muscular Dystrophy Association (to D. W. S. and D. E. D.). 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.

^¶ To whom correspondence should be addressed. Tel.: 215-898-4809; Fax: 215-573-2093; E-mail: discher{at}seas.upenn.edu.

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