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J. Biol. Chem., Vol. 278, Issue 42, 41019-41027, October 17, 2003

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Complete Alanine Scanning of Intersubunit Interfaces in a Foot-and-Mouth Disease Virus Capsid Reveals Critical Contributions of Many Side Chains to Particle Stability and Viral Function^*

Roberto Mateo , Ana Díaz, Eric Baranowski  and Mauricio G. Mateu ¶

From the Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain

Spherical virus capsids are large, multimeric protein shells whose assembly and stability depend on the establishment of multiple non-covalent interactions between many polypeptide subunits. In a foot-and-mouth disease virus capsid, 42 amino acid side chains per protomer are involved in noncovalent interactions between pentameric subunits that function as assembly/disassembly intermediates. We have individually truncated to alanine these 42 side chains and assessed their relevance for completion of the virus life cycle and capsid stability. Most mutations provoked a drastic reduction in virus yields. Nearly all of these critical mutations led to virions whose thermal inactivation rates differed from that of the parent virus, and many affected also early steps in the viral cycle. Rapid selection of genotypic revertants or variants with forward or compensatory mutations that restored viability was occasionally detected. The results with this model virus indicate the following. (i) Most of the residues at the interfaces between capsid subunits are critically important for viral function, in part but not exclusively because of their involvement in intersubunit recognition. Each hydrogen bond and salt bridge buried at the subunit interfaces may be important for capsid stability. (ii) New mutations able to restore viability may arise frequently at the subunit interfaces during virus evolution. (iii) A few interfacial side chains are functionally tolerant to truncation and may provide adequate mutation sites for the engineering of a thermostable capsid, potentially useful as an improved vaccine.

Received for publication, May 13, 2003 , and in revised form, June 25, 2003.

^* This work was supported in part by MCyT Grant BIO2000-0408, Comunidad de Madrid Grants 07B/0008/1999 and 08.2/0008.2/2000 (to M. G. M.), and by an institutional grant from Fundación Ramón Areces. 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.

Recipient of a predoctoral fellowship from Gobierno Vasco.

Present address: Institut National de la Recherche Agronomique, UMR 1225, Ecole Nationale Vétérinaire, 23 Chemin des Capelles, 31076 Toulouse Cedex 3, France.

^¶ To whom correspondence should be addressed. Tel.: 34-91-3978462; Fax: 34-91-3974799; E-mail: mgarcia{at}cbm.uam.es.

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