PDBsum entry 2me4

Membrane protein

PDB id: 2me4

Contents

Protein chain

27 a.a.

PDB id:

2me4

Name:

Membrane protein

Title:

HIV-1 gp41 cladE C membrane proximal external region peptide in dpc micelle

Structure:

Envelope glycoprotein gp160. Chain: a. Fragment: membrane proximal external region (unp residues 671-697). Synonym: mper-pb7. Engineered: yes

Source:

Human immunodeficiency virus 1. Organism_taxid: 11676. Strain: cladE C, zm197m.Pb7 isolate. Gene: env. Expressed in: escherichia coli. Expression_system_taxid: 469008.

NMR struc:

10 models

Authors:

Z.J.Sun,G.Wagner,E.L.Reinherz,M.Kim,L.Song,J.Choi,Y.Cheng, B.Chowdhury,G.Bellot,W.Shih

Key ref:

Z.Y.Sun et al. (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. J Mol Biol, 426, 1095-1108. PubMed id: 24075869 DOI: 10.1016/j.jmb.2013.09.030

Date:

20-Sep-13 Release date: 09-Oct-13

Protein chain

Q27Q69  (Q27Q69_HV1) -  Envelope glycoprotein gp160 from Human immunodeficiency virus type 1

Seq: 877 a.a.

Struc: 27 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1016/j.jmb.2013.09.030

J Mol Biol 426:1095-1108 (2014)

PubMed id: 24075869

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.

Z.Y.Sun, Y.Cheng, M.Kim, L.Song, J.Choi, U.J.Kudahl, V.Brusic, B.Chowdhury, L.Yu, M.S.Seaman, G.Bellot, W.M.Shih, G.Wagner, E.L.Reinherz.

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.