title: Distinct mechanisms of lipid bilayer perturbation induced by peptides derived from the membrane-proximal external region of HIV-1 gp41.
abstract: The conserved, membrane-proximal external region (MPER) of the human immunodeficiency virus type-1 envelope glycoprotein 41 subunit is required for fusogenic activity. It has been proposed that MPER functions by disrupting the virion membrane. Supporting its critical role in viral entry as a membrane-bound entity, MPER constitutes the target for broadly neutralizing antibodies that have evolved mechanisms to recognize membrane-inserted epitopes. We have analyzed here the molecular mechanisms of membrane permeabilization induced by N-preTM and PreTM-C, two peptides derived from MPER sequences showing a tendency to associate with the bilayer interface or to transfer into the hydrocarbon core, respectively. Both peptides contained the full epitope sequence recognized by the 4E10 monoclonal antibody (MAb4E10), which was subsequently used to probe peptide accessibility from the water phase. Capacities of N-preTM and PreTM-C for associating with vesicles and inducing their permeabilization were comparable. However, MAb4E10 specifically blocked the permeabilization induced by N-preTM but did not appreciably affect that induced by PreTM-C. Supporting the existence of different membrane-bound lytic structures, N-preTM was running as a monomer on SDS-PAGE and induced the graded release of vesicular contents, whereas PreTM-C migrated on SDS-PAGE as dimers and permeabilized vesicles following an all-or-none mechanism, reminiscent of that underlying melittin-induced membrane lysis. These results support the functional segmentation of gp41 membrane regions into hydrophobic subdomains, which might expose neutralizing epitopes and induce membrane-disrupting effects following distinct patterns during the fusion cascade.
authors.affiliation: Unidad de Biofisica (CSIC-UPV/EHU) and Departamento de Bioquimica, Universidad del Pais Vasco, Aptdo. 644, 48080 Bilbao, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Apellániz
authors.forename: Shlomo
authors.initials: S
authors.lastname: Nir
authors.forename: José L
authors.initials: JL
authors.lastname: Nieva
mesh_terms: D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000378:metabolism*; D002463:Cell Membrane Permeability; D000939:Epitopes / Q000737:chemistry / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers / Q000378:metabolism*; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D013816:Thermodynamics
chemical_list: D000939:Epitopes; D015700:HIV Envelope Protein gp41; D008051:Lipid Bilayers; D010455:Peptides; C514787:gp41 protein, Human immunodeficiency virus 1