title: Structural and functional roles of HIV-1 gp41 pretransmembrane sequence segmentation.
abstract: The membrane-proximal segment connecting the helical core with the transmembrane anchor of human immunodeficiency virus type 1 gp41 is accessible to broadly neutralizing antibodies and plays a crucial role in fusion activity. New predictive approaches including computation of interfacial affinity and the corresponding hydrophobic moments suggest that this region is functionally segmented into two consecutive subdomains: one amphipathic at the N-terminal side and one fully interfacial at the C-terminus. The N-terminal subdomain would extend alpha-helices from the preceding carboxy-terminal heptad repeat and provide, at the same time, a hydrophobic-at-interface surface. Experiments were performed to compare a wild-type representing pretransmembrane peptide with a nonamphipathic defective sequence, which otherwise conserved interfacial hydrophobicity at the carboxy-subdomain. Results confirmed that both penetrated equally well into lipid monolayers and both were able to partition into membrane interfaces. However only the functional sequence: 1), adopted helical structures in solution and in membranes; 2), formed homo-oligomers in solution and membranes; and 3), inhibited gp41-induced cell-cell fusion. These data support two roles for gp41 aromatic-rich pretransmembrane sequence: 1), oligomerization of gp41; and 2), immersion into the viral membrane interface. Accessibility to membrane interfaces and subsequent adoption of the low-energy structure may augment helical bundle formation and perhaps be related to a concomitant loss of immunoreactivity. These results may have implications in the development of HIV-1 fusion inhibitors and vaccines.
authors.affiliation: Unidad de Biofísica (CSIC-UPV/EHU) and Departamento de Bioquímica, Universidad del País Vasco, 48080 Bilbao, Spain.
authors.forename: Asier
authors.initials: A
authors.lastname: Sáez-Cirión
authors.forename: José L R
authors.initials: JL
authors.lastname: Arrondo
authors.forename: María J
authors.initials: MJ
authors.lastname: Gómara
authors.forename: Maier
authors.initials: M
authors.lastname: Lorizate
authors.forename: Ibón
authors.initials: I
authors.lastname: Iloro
authors.forename: Grigory
authors.initials: G
authors.lastname: Melikyan
authors.forename: José L
authors.initials: JL
authors.lastname: Nieva
mesh_terms: D055592:Biophysical Phenomena; D001703:Biophysics; D002459:Cell Fusion; D002462:Cell Membrane / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008954:Models, Biological; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013055:Spectrophotometry, Infrared; D017550:Spectroscopy, Fourier Transform Infrared; D013329:Structure-Activity Relationship
chemical_list: D015700:HIV Envelope Protein gp41; D008055:Lipids; D010455:Peptides