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J. Biol. Chem., Vol. 280, Issue 46, 38528-38536, November 18, 2005

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A General Model for Preferential Hetero-oligomerization of LIN-2/7 Domains

MECHANISM UNDERLYING DIRECTED ASSEMBLY OF SUPRAMOLECULAR SIGNALING COMPLEXES^*

Keiko Y. Petrosky, Horng D. Ou, Frank Löhr, Volker Dötsch, and Wendell A. Lim¶1

From the Biophysics Graduate Program and the ^¶Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94143 and the Institute for Biophysical Chemistry, University of Frankfurt, Frankfurt am Main, 60439 Germany

LIN-2/7 (L27) domains are protein interaction modules that preferentially hetero-oligomerize, a property critical for their function in directing specific assembly of supramolecular signaling complexes at synapses and other polarized cell-cell junctions. We have solved the solution structure of the heterodimer composed of the L27 domains from LIN-2 and LIN-7. Comparison of this structure with other L27 domain structures has allowed us to formulate a general model for why most L27 domains form an obligate heterodimer complex. L27 domains can be divided in two types (A and B), with each heterodimer comprising an A/B pair. We have identified two keystone positions that play a central role in discrimination. The residues at these positions are energetically acceptable in the context of an A/B heterodimer, but would lead to packing defects or electrostatic repulsion in the context of A/A and B/B homodimers. As predicted by the model, mutations of keystone residues stabilize normally strongly disfavored homodimers. Thus, L27 domains are specifically optimized to avoid homodimeric interactions.

Received for publication, June 15, 2005 , and in revised form, August 12, 2005.

The atomic coordinates and structure factors (code 1ZL8) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* 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.

¹ To whom correspondence should be addressed: Dept. of Cellular and Molecular Pharmacology, University of California, 600 16th St., San Francisco, CA 94143. Tel.: 415-502-8080; Fax: 415-514-4242; E-mail: wlim{at}itsa.ucsf.edu.

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