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

Zhen Yu J Sun, Yuxing Cheng, Mikyung Kim, Likai Song, Jaewon Choi, Ulrich J. Kudahl, Vladimir Brusic, Barnali Chowdhury, Lu Yu, Michael S. Seaman, Gaëtan Bellot, William M. Shih, Gerhard Wagner, Ellis L. Reinherz

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1095-1108
Number of pages14
JournalJournal of Molecular Biology
Volume426
Issue number5
DOIs
Publication statusPublished - Mar 6 2014
Externally publishedYes

Fingerprint

Virus Internalization
HIV-1
Membranes
Joints
Viruses
Amino Acids
Lentivirus
Mutation
Cell Fusion
Alanine
Virion
T-Lymphocytes
Lipids
Antibodies
Proteins

Keywords

  • broadly neutralizing antibody
  • helix capping
  • helix-hinge-helix motif
  • NMR solution structure
  • viral membrane fusion

ASJC Scopus subject areas

  • Molecular Biology

Cite this

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. / Sun, Zhen Yu J; Cheng, Yuxing; Kim, Mikyung; Song, Likai; Choi, Jaewon; Kudahl, Ulrich J.; Brusic, Vladimir; Chowdhury, Barnali; Yu, Lu; Seaman, Michael S.; Bellot, Gaëtan; Shih, William M.; Wagner, Gerhard; Reinherz, Ellis L.

In: Journal of Molecular Biology, Vol. 426, No. 5, 06.03.2014, p. 1095-1108.

Research output: Contribution to journalArticle

Sun, ZYJ, Cheng, Y, Kim, M, Song, L, Choi, J, Kudahl, UJ, Brusic, V, Chowdhury, B, Yu, L, Seaman, MS, Bellot, G, Shih, WM, Wagner, G & Reinherz, EL 2014, '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', Journal of Molecular Biology, vol. 426, no. 5, pp. 1095-1108. https://doi.org/10.1016/j.jmb.2013.09.030
Sun, Zhen Yu J ; Cheng, Yuxing ; Kim, Mikyung ; Song, Likai ; Choi, Jaewon ; Kudahl, Ulrich J. ; Brusic, Vladimir ; Chowdhury, Barnali ; Yu, Lu ; Seaman, Michael S. ; Bellot, Gaëtan ; Shih, William M. ; Wagner, Gerhard ; Reinherz, Ellis L. / 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. In: Journal of Molecular Biology. 2014 ; Vol. 426, No. 5. pp. 1095-1108.
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AU - Sun, Zhen Yu J

AU - Cheng, Yuxing

AU - Kim, Mikyung

AU - Song, Likai

AU - Choi, Jaewon

AU - Kudahl, Ulrich J.

AU - Brusic, Vladimir

AU - Chowdhury, Barnali

AU - Yu, Lu

AU - Seaman, Michael S.

AU - Bellot, Gaëtan

AU - Shih, William M.

AU - Wagner, Gerhard

AU - Reinherz, Ellis L.

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N2 - 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.

AB - 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.

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KW - NMR solution structure

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