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J. Biol. Chem., Vol. 283, Issue 24, 16561-16572, June 13, 2008

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Functional Interaction between Paramyxovirus Fusion and Attachment Proteins^*

Jin K. Lee, Andrew Prussia, Tanja Paal, Laura K. White, James P. Snyder, and Richard K. Plemper¹

From the Department of Pediatrics, Emory University School of Medicine and the Department of Chemistry, Emory University, Atlanta, Georgia 30322

Paramyxovirinae envelope glycoproteins constitute a premier model to dissect how specific and dynamic interactions in multisubunit membrane protein complexes can control deep-seated conformational rearrangements. However, individual residues that determine reciprocal specificity of the viral attachment and fusion (F) proteins have not been identified. We have developed an assay based on a pair of canine distemper virus (CDV) F proteins (strains Onderstepoort (ODP) and Lederle) that share 95% identity but differ in their ability to form functional complexes with the measles virus (MV) attachment protein (H). Characterization of CDV F chimeras and mutagenesis reveals four residues in CDV F-ODP (positions 164, 219, 233, and 317) required for productive interaction with MV H. Mutating these residues to the Lederle type disrupts triggering of F-ODP by MV H without affecting functionality when co-expressed with CDV H. Co-immunoprecipitation shows a stronger physical interaction of F-ODP than F-Lederle with MV H. Mutagenesis of MV F highlights the MV residues homologous to CDV F residues 233 and 317 as determinants for physical glycoprotein interaction and fusion activity under homotypic conditions. In assay reversal, the introduction of sections of the CDV H stalk into MV H shows a five-residue fragment (residues 110–114) to mediate specificity for CDV F-Lederle. All of the MV H stalk chimeras are surface-expressed, show hemadsorption activity, and trigger MV F. Combining the five-residue H chimera with the CDV F-ODP quadruple mutant partially restores activity, indicating that the residues identified in either glycoprotein contribute interdependently to the formation of functional complexes. Their localization in structural models of F and H suggests that placement in particular of F residue 233 in close proximity to the 110–114 region of H is structurally conceivable.

Received for publication, February 7, 2008 , and in revised form, April 16, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants AI056179 and AI071002 (to R. K. P.). 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 methods and supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed: 2015 Uppergate Dr., Ste. 520, Emory University, Atlanta, GA 30322. Fax: 404-727-9223; E-mail: rplempe{at}emory.edu.

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