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Fully hydrophobic HIV gp41 adopts a hemifusion-like conformation in phospholipid bilayers
Journal article   Open access   Peer reviewed

Fully hydrophobic HIV gp41 adopts a hemifusion-like conformation in phospholipid bilayers

Myungwoon Lee, Chloe A Morgan and Mei Hong
The Journal of biological chemistry, v 294(40), pp 14732-14744
04 Oct 2019
DOI: https://doi.org/10.1074/jbc.RA119.009542
PMID: 31409642
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1074/jbc.RA119.009542View
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Abstract

Cell Membrane - chemistry Cell Membrane - genetics Gene Expression Regulation, Viral - genetics HIV Envelope Protein gp41 - chemistry HIV Envelope Protein gp41 - genetics HIV Infections - genetics HIV Infections - virology HIV-1 - chemistry HIV-1 - genetics Humans Hydrophobic and Hydrophilic Interactions Lipid Bilayers - chemistry Models, Molecular Phospholipids - chemistry Phospholipids - genetics Protein Conformation Protein Conformation, alpha-Helical Protein Conformation, beta-Strand Protein Domains - genetics Virus Internalization Water - chemistry
The HIV envelope glycoprotein mediates virus entry into target cells by fusing the virus lipid envelope with the cell membrane. This process requires large-scale conformational changes of the fusion protein gp41. Current understanding of the mechanisms with which gp41 induces membrane merger is limited by the fact that the hydrophobic N-terminal fusion peptide (FP) and C-terminal transmembrane domain (TMD) of the protein are challenging to characterize structurally in the lipid bilayer. Here we have expressed a gp41 construct that contains both termini, including the FP, the fusion peptide-proximal region (FPPR), the membrane-proximal external region (MPER), and the TMD. These hydrophobic domains are linked together by a shortened water-soluble ectodomain. We reconstituted this "short NC" gp41 into a virus-mimetic lipid membrane and conducted solid-state NMR experiments to probe the membrane-bound conformation and topology of the protein. C chemical shifts indicate that the C-terminal MPER-TMD is predominantly α-helical, whereas the N-terminal FP-FPPR exhibits β-sheet character. Water and lipid H polarization transfer to the protein revealed that the TMD is well-inserted into the lipid bilayer, whereas the FPPR and MPER are exposed to the membrane surface. Importantly, correlation signals between the FP-FPPR and the MPER are observed, providing evidence that the ectodomain is sufficiently collapsed to bring the N- and C-terminal hydrophobic domains into close proximity. These results support a hemifusion-like model of the short NC gp41 in which the ectodomain forms a partially folded hairpin that places the FPPR and MPER on the opposing surfaces of two lipid membranes.

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Collaboration types
Domestic collaboration
Web of Science research areas
Biochemistry & Molecular Biology
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