Fully Hydrophobic HIV gp41 Adopts a Hemifusion-Like Conformation in Phospholipid Bilayers
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1-s2.0-S0021925820350225-main.pdf
Description
Published version
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5.88 MB
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Adobe PDF
Checksum (MD5)
25d3a935a687e50045163f2e7bfdcd64
Author(s)
Lee, Myungwoon
Morgan, Chloe A
Hong, Mei
Date Issued
2019
Journal
Journal of Biological Chemistry
Publisher
Elsevier BV
Citation
Lee, Myungwoon, Morgan, Chloe A and Hong, Mei. 2019. "Fully Hydrophobic HIV gp41 Adopts a Hemifusion-Like Conformation in Phospholipid Bilayers." Journal of Biological Chemistry, 294 (40).
Version
Final published version
Abstract
© 2019 Lee et al. 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-stateNMRexperiments to probe the membrane-bound conformation and topology of the protein. 13C 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 1H 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.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
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Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1074/JBC.RA119.009542
