Journal Article

Disruption of the HIV-1 Envelope allosteric network blocks CD4-induced rearrangements

Han, Qifeng, Acharya, Priyamvada, Hsu, Allen L., Parks, Robert, Saunders, Kevin O., Edwards, R J, Henderson, Rory, Mothes, Walther, Lu, Maolin, Borgnia, Mario J., Blanchard, Scott C., Mu, Zekun, Carter, Elizabeth, Munir Alam, S., Zhou, Ye, Wiehe, Kevin, Bartesaghi, Alberto, Haynes, Barton F.

2020

Overview

The trimeric HIV-1 Envelope protein (Env) mediates viral-host cell fusion via a network of conformational transitions, with allosteric elements in each protomer orchestrating host receptor-induced exposure of the co-receptor binding site and fusion elements. To understand the molecular details of this allostery, here, we introduce Env mutations aimed to prevent CD4-induced rearrangements in the HIV-1 BG505 Env trimer. Binding analysis and single−molecule Förster Resonance Energy Transfer confirm that these mutations prevent CD4-induced transitions of the HIV-1 Env. Structural analysis by single−particle cryo-electron microscopy performed on the BG505 SOSIP mutant Env proteins shows rearrangements in the gp120 topological layer contacts with gp41. Displacement of a conserved tryptophan (W571) from its typical pocket in these Env mutants renders the Env insensitive to CD4 binding. These results reveal the critical function of W571 as a conformational switch in Env allostery and receptor-mediated viral entry and provide insights on Env conformation that are relevant for vaccine design. Here, using cryo-EM and smFRET, Henderson et al. show how tryptophan 571 in the HIV-1 Env acts as a conformational switch during receptor-mediated viral entry and design HIV-1 Env proteins that cannot undergo conformational changes. This has important implications for HIV-1 vaccine design.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/1 / 101/28 / 13/31 / 631/250/590/2294 / 631/326/596/2148 / 631/535/1258/1259 / 692/699/255/1901 / Allosteric properties / Allosteric Regulation / Amino Acid Sequence / Binding sites / CD4 antigen / CD4 Antigens - metabolism / Cell fusion / Design / Disruption / Electron microscopy / Energy transfer / env Gene Products, Human Immunodeficiency Virus - chemistry / env Gene Products, Human Immunodeficiency Virus - metabolism / env Gene Products, Human Immunodeficiency Virus - ultrastructure / Glycoprotein gp120 / Glycoprotein gp41 / HIV / HIV-1 - metabolism / Human immunodeficiency virus / Humanities and Social Sciences / Humans / Models, Molecular / multidisciplinary / Mutant Proteins - chemistry / Mutant Proteins - metabolism / Mutation / Mutation - genetics / Protein Binding / Protein Domains / Protein Multimerization / Protein Stability / Proteins / Science / Science (multidisciplinary) / Solubility / Structural analysis / Temperature / Trimers / Tryptophan / Vaccines / Viral envelope proteins