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Biophysical analysis of the MHR motif in folding and domain swapping of the HIV capsid protein C-terminal domain.

Abstract
Infection by human immunodeficiency virus (HIV) depends on the function, in virion morphogenesis and other stages of the viral cycle, of a highly conserved structural element, the major homology region (MHR), within the carboxyterminal domain (CTD) of the capsid protein. In a modified CTD dimer, MHR is swapped between monomers. While no evidence for MHR swapping has been provided by structural models of retroviral capsids, it is unknown whether it may occur transiently along the virus assembly pathway. Whatever the case, the MHR-swapped dimer does provide a novel target for the development of anti-HIV drugs based on the concept of trapping a nonnative capsid protein conformation. We have carried out a thermodynamic and kinetic characterization of the domain-swapped CTD dimer in solution. The analysis includes a dissection of the role of conserved MHR residues and other amino acids at the dimerization interface in CTD folding, stability, and dimerization by domain swapping. The results revealed some energetic hotspots at the domain-swapped interface. In addition, many MHR residues that are not in the protein hydrophobic core were nevertheless found to be critical for folding and stability of the CTD monomer, which may dramatically slow down the swapping reaction. Conservation of MHR residues in retroviruses did not correlate with their contribution to domain swapping, but it did correlate with their importance for stable CTD folding. Because folding is required for capsid protein function, this remarkable MHR-mediated conformational stabilization of CTD may help to explain the functional roles of MHR not only during immature capsid assembly but in other processes associated with retrovirus infection. This energetic dissection of the dimerization interface in MHR-swapped CTD may also facilitate the design of anti-HIV compounds that inhibit capsid assembly by conformational trapping of swapped CTD dimers.
AuthorsRebeca Bocanegra, Miguel Ángel Fuertes, Alicia Rodríguez-Huete, José Luis Neira, Mauricio G Mateu
JournalBiophysical journal (Biophys J) Vol. 108 Issue 2 Pg. 338-49 (Jan 20 2015) ISSN: 1542-0086 [Electronic] United States
PMID25606682 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 Biophysical Society. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Capsid Proteins
Topics
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Capsid Proteins (chemistry)
  • HIV (chemistry)
  • Molecular Sequence Data
  • Protein Folding
  • Protein Multimerization
  • Protein Stability
  • Protein Structure, Tertiary

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