Lethal mutations in the major homology region and their suppressors act by modulating the dimerization of the rous sarcoma virus capsid protein C-terminal domain

Paula M. Dalessio, Rebecca C. Craven, Parvez M. Lokhandwala, Ira J. Ropson

Research output: Contribution to journalArticle

Abstract

An infective retrovirus requires a mature capsid shell around the viral replication complex. This shell is formed by about 1500 capsid protein monomers, organized into hexamer and pentamer rings that are linked to each other by the dimerization of the C-terminal domain (CTD). The major homology region (MHR), the most highly conserved protein sequence across retroviral genomes, is part of the CTD. Several mutations in the MHR appear to block infectivity by preventing capsid formation. Suppressor mutations have been identified that are distant in sequence and structure from the MHR and restore capsid formation. The effects of two lethal and two suppressor mutations on the stability and function of the CTD were examined. No correlation with infectivity was found for the stability of the lethal mutations (D155Y-CTD, F167Y-CTD) and suppressor mutations (R185W-CTD, I190V-CTD). The stabilities of three double mutant proteins (D155Y/R185W-CTD, F167Y/R185W-CTD, and F167Y/I190V-CTD) were additive. However, the dimerization affinity of the mutant proteins correlated strongly with biological function. The CTD proteins with lethal mutations did not dimerize, while those with suppressor mutations had greater dimerization affinity than WT-CTD. The suppressor mutations were able to partially correct the dimerization defect caused by the lethal MHR mutations in double mutant proteins. Despite their dramatic effects on dimerization, none of these residues participate directly in the proposed dimerization interface in a mature capsid. These findings suggest that the conserved sequence of the MHR has critical roles in the conformation(s) of the CTD that are required for dimerization and correct capsid maturation.

Original languageEnglish (US)
Pages (from-to)316-325
Number of pages10
JournalProteins: Structure, Function and Bioinformatics
Volume81
Issue number2
DOIs
StatePublished - Feb 2013

Keywords

  • Protein dimerization
  • Protein mutagenesis
  • Protein stability
  • Retroviral capsid protein

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology

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