Peptide mimic of the HIV envelope gp120-gp41 interface.
The human immunodeficiency virus envelope glycoprotein (Env) is composed of surface (gp120) and transmembrane (gp41) subunits, which are noncovalently associated on the viral surface. Human immunodeficiency virus Env mediates viral entry after undergoing a complex series of conformational changes induced by interaction with cellular CD4 and a chemokine coreceptor. These changes propagate from gp120 to gp41 via the gp120-gp41 interface, ultimately exposing gp41 and allowing it to form the trimer-of-hairpins structure that provides the driving force for membrane fusion. Key unresolved questions about the gp120-gp41 interface include the specific regions of gp41 and gp120 involved, the mechanism by which receptor and coreceptor-binding-induced conformational changes in gp120 are communicated to gp41, how trimer-of-hairpins formation is prevented in the prefusogenic gp120-gp41 complex, and, ultimately, the structure of the prefusion gp120-gp41 complex. Here, we develop a biochemical model system that mimics a key portion of the gp120-gp41 interface in the prefusogenic state. We find that a gp41 fragment containing the disulfide bond loop and C-peptide region binds primarily to the gp120 C5 region and that this interaction is incompatible with trimer-of-hairpins formation. Based on these data, we propose that in prefusogenic Env, gp120 sequesters the gp41 C-peptide region away from the N-trimer region, preventing trimer-of-hairpins formation until coreceptor binding disrupts this interface. This model system is a valuable tool for studying the gp120-gp41 complex, conformational changes induced by CD4 and coreceptor binding, and the mechanism of membrane fusion.
Kim
Sunghwan
S
Department of Biochemistry, University of Utah School of Medicine, 15 North Medical Drive East, Room 4100, Salt Lake City, UT 84112-5650, USA.
Pang
Hong-Bo
HB
Kay
Michael S
MS
D015704:CD4 Antigens / Q000378:metabolism; D004220:Disulfides; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D010455:Peptides; D011487:Protein Conformation; D025941:Protein Interaction Mapping
D015704:CD4 Antigens; D004220:Disulfides; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D010455:Peptides