title: The HIV gp41 pocket binding domain enables C-terminal heptad repeat transition from mediating membrane fusion to immune modulation.
abstract: For successful infection and propagation viruses must overcome many obstacles such as the immune system and entry into their host cells. HIV utilizes its trimeric envelope protein gp160, specifically the gp41 subunit, to enter its host cell. During this process, a gp41-central coiled coil is formed from three N- and three C-terminal heptad repeats, termed the six-helix bundle (SHB), which drives membrane fusion. Recently, T-cell suppression has been reported as an additional function for several regions of gp41 by interfering with the T-cell receptor (TCR) signalling cascade. One of these regions encompasses the conserved pocket binding domain (PBD) that is situated in the C-terminal heptad repeat (CHR) and stabilizes SHB formation. This could indicate that the PBD plays a role in T-cell suppression in addition to its role in membrane fusion. To investigate this dual function, we used two independent cell cultures coupled with biophysical techniques. The data reveal that the PBD mediates T-cell suppression by stabilizing a TCR-binding conformation in the membrane. Moreover, we show that the clinically used HIV fusion inhibitor T-20 did not show suppressive abilities, in contrast with the potent fusion inhibitor C34. In addition, by focusing on SHB conformation after its assembly, we shed light on a mechanism by which gp41's function alternates from membrane fusion facilitation to suppression of TCR activation.
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Yoel A
authors.initials: YA
authors.lastname: Klug
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Gal
authors.initials: G
authors.lastname: Kapach
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Etai
authors.initials: E
authors.lastname: Rotem
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dubreuil
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 7610001, Israel Yechiel.Shai@weizmann.ac.il.
authors.forename: Yechiel
authors.initials: Y
authors.lastname: Shai
mesh_terms: D000818:Animals; D015700:HIV Envelope Protein gp41 / Q000235:genetics / Q000276:immunology*; D023581:HIV Fusion Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D010455:Peptides / Q000235:genetics / Q000276:immunology*; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D020449:Repetitive Sequences, Amino Acid; D053586:Virus Internalization
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; C514787:gp41 protein, Human immunodeficiency virus 1
keywords: biophysics; fusion inhibitors; immune suppression; membrane proteins; virus cell interaction