Structural and functional roles of HIV-1 gp41 pretransmembrane sequence segmentation

Area of Science:

• Virology
• Structural Biology
• Biochemistry

Background:

• The membrane-proximal segment of human immunodeficiency virus type 1 (HIV-1) gp41 is crucial for viral fusion.
• This segment connects the helical core to the transmembrane anchor and is targeted by broadly neutralizing antibodies.

Purpose of the Study:

• To investigate the functional segmentation of the HIV-1 gp41 membrane-proximal segment.
• To elucidate the roles of different subdomains in fusion activity and oligomerization.

Main Methods:

• Computational prediction of interfacial affinity and hydrophobic moments.
• Experimental comparison of wild-type and nonamphipathic mutant peptides using lipid monolayers and membrane interface partitioning.
• Analysis of helical structure adoption, homo-oligomerization, and inhibition of cell-cell fusion.

Main Results:

• Both wild-type and mutant peptides penetrated lipid monolayers and partitioned into membrane interfaces.
• Only the functional wild-type peptide adopted helical structures, formed homo-oligomers, and inhibited gp41-induced cell-cell fusion.
• The N-terminal subdomain is amphipathic, while the C-terminal subdomain is interfacial.

Conclusions:

• The aromatic-rich pretransmembrane sequence of gp41 has dual roles: oligomerization and immersion into the viral membrane interface.
• Accessibility to membrane interfaces and adoption of low-energy structures may enhance helical bundle formation and reduce immunoreactivity.
• Findings have implications for developing novel HIV-1 fusion inhibitors and vaccines.