title: The highly conserved layer-3 component of the HIV-1 gp120 inner domain is critical for CD4-required conformational transitions.
abstract: The trimeric envelope glycoprotein (Env) of human immunodeficiency virus type 1 (HIV-1) mediates virus entry into host cells. CD4 engagement with the gp120 exterior envelope glycoprotein subunit represents the first step during HIV-1 entry. CD4-induced conformational changes in the gp120 inner domain involve three potentially flexible topological layers (layers 1, 2, and 3). Structural rearrangements between layer 1 and layer 2 have been shown to facilitate the transition of the envelope glycoprotein trimer from the unliganded to the CD4-bound state and to stabilize gp120-CD4 interaction. However, our understanding of CD4-induced conformational changes in the gp120 inner domain remains incomplete. Here, we report that a highly conserved element of the gp120 inner domain, layer 3, plays a pivot-like role in these allosteric changes. In the unliganded state, layer 3 modulates the association of gp120 with the Env trimer, probably by influencing the relationship of the gp120 inner and outer domains. Importantly, layer 3 governs the efficiency of the initial gp120 interaction with CD4, a function that can also be fulfilled by filling the Phe43 cavity. This work defines the functional importance of layer 3 and completes a picture detailing the role of the gp120 inner domain in CD4-induced conformational transitions in the HIV-1 Env trimer.
authors.affiliation: Centre de Recherche du CHUM, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Anik
authors.initials: A
authors.lastname: Désormeaux
authors.forename: Mathieu
authors.initials: M
authors.lastname: Coutu
authors.forename: Halima
authors.initials: H
authors.lastname: Medjahed
authors.forename: Beatriz
authors.initials: B
authors.lastname: Pacheco
authors.forename: Alon
authors.initials: A
authors.lastname: Herschhorn
authors.forename: Christopher
authors.initials: C
authors.lastname: Gu
authors.forename: Shi-Hua
authors.initials: SH
authors.lastname: Xiang
authors.forename: Youdong
authors.initials: Y
authors.lastname: Mao
authors.forename: Joseph
authors.initials: J
authors.lastname: Sodroski
authors.forename: Andrés
authors.initials: A
authors.lastname: Finzi
mesh_terms: D000818:Animals; D001665:Binding Sites; D015704:CD4 Antigens / Q000378:metabolism*; D002460:Cell Line; D018360:Crystallography, X-Ray; D004285:Dogs; D057809:HEK293 Cells; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D053586:Virus Internalization
chemical_list: D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120