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J Mol Biol. 2014 Mar 6;426(5):1095-108. doi: 10.1016/j.jmb.2013.09.030. Epub 2013 Sep 26.

Disruption of helix-capping residues 671 and 674 reveals a role in HIV-1 entry for a specialized hinge segment of the membrane proximal external region of gp41.

Author information

1
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
2
Laboratory of Immunobiology and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
3
Laboratory of Immunobiology and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
4
National High Magnetic Field Laboratory, Florida State University, Tallahassee, FL 32310, USA.
5
Cancer Vaccine Center and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
6
Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Cancer Vaccine Center and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
7
Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
8
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Wyss Institute for Biologically Inspired Engineering at Harvard, Boston, MA 02115, USA.
9
Laboratory of Immunobiology and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Electronic address: Ellis_Reinherz@dfci.harvard.edu.

Abstract

HIV-1 (human immunodeficiency virus type 1) uses its trimeric gp160 envelope (Env) protein consisting of non-covalently associated gp120 and gp41 subunits to mediate entry into human T lymphocytes. A facile virus fusion mechanism compensates for the sparse Env copy number observed on viral particles and includes a 22-amino-acid, lentivirus-specific adaptation at the gp41 base (amino acid residues 662-683), termed the membrane proximal external region (MPER). We show by NMR and EPR that the MPER consists of a structurally conserved pair of viral lipid-immersed helices separated by a hinge with tandem joints that can be locked by capping residues between helices. This design fosters efficient HIV-1 fusion via interconverting structures while, at the same time, affording immune escape. Disruption of both joints by double alanine mutations at Env positions 671 and 674 (AA) results in attenuation of Env-mediated cell-cell fusion and hemifusion, as well as viral infectivity mediated by both CD4-dependent and CD4-independent viruses. The potential mechanism of disruption was revealed by structural analysis of MPER conformational changes induced by AA mutation. A deeper acyl chain-buried MPER middle section and the elimination of cross-hinge rigid-body motion almost certainly impede requisite structural rearrangements during the fusion process, explaining the absence of MPER AA variants among all known naturally occurring HIV-1 viral sequences. Furthermore, those broadly neutralization antibodies directed against the HIV-1 MPER exploit the tandem joint architecture involving helix capping, thereby disrupting hinge function.

KEYWORDS:

NMR solution structure; broadly neutralizing antibody; helix capping; helix–hinge–helix motif; viral membrane fusion

PMID:
24075869
PMCID:
PMC3934758
DOI:
10.1016/j.jmb.2013.09.030
[Indexed for MEDLINE]
Free PMC Article

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