Domain-swapped dimerization of the HIV-1 capsid C-terminal domain

doi:10.1073/pnas.0609477104

Domain-swapped dimerization of the HIV-1 capsid C-terminal domain

*Department of Pathology, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115;
^†Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115; and
^¶Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 660 South Euclid Avenue, Box 8231, St. Louis, MO 63110

Edited by Gregory A. Petsko, Brandeis University, Waltham, MA, and approved January 18, 2007 (received for review October 25, 2006)

Abstract

Assembly of the HIV and other retroviruses is primarily driven by the oligomerization of the Gag polyprotein, the major viral structural protein capable of forming virus-like particles even in the absence of all other virally encoded components. Several critical determinants of Gag oligomerization are located in the C-terminal domain of the capsid protein (CA-CTD), which encompasses the most conserved segment in the highly variable Gag protein called the major homology region (MHR). The CA-CTD is thought to function as a dimerization module, although the existing model of CA-CTD dimerization does not readily explain why the conserved residues of the MHR are essential for retroviral assembly. Here we describe an x-ray structure of a distinct domain-swapped variant of the HIV-1 CA-CTD dimer stabilized by a single amino acid deletion. In the domain-swapped structure, the MHR-containing segment forms a major part of the dimerization interface, providing a structural mechanism for the enigmatic function of the MHR in HIV assembly. Our observations suggest that swapping of the MHR segments of adjacent Gag molecules may be a critical intermediate in retroviral assembly.

Footnotes

^‡To whom correspondence should be addressed. E-mail: dmitri_ivanov{at}hms.harvard.edu
Author contributions: D.I. and O.V.T. contributed equally to this work; D.I., G.W., and T.C. designed research; D.I., O.V.T., and J.K. performed research; J.K. contributed new reagents/analytic tools; D.I. and O.V.T. analyzed data; and D.I., O.V.T., T.E., G.W., and T.C. wrote the paper.
↵ ^§Present address: Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48130.
The authors declare no conflict of interest.
This article is a PNAS direct submission.
Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.pdb.org (PDB ID code 2ONT).
Abbreviations:

CA,

capsid protein;

CA-CTD,

C-terminal domain of the CA;

MHR,

major homology region;

SP1,

spacer peptide 1.