The Highly Conserved Layer-3 Component of the HIV-1 gp120 Inner Domain Is Critical for CD4-Required Conformational Transitions

Authors

Anik Désormeaux, Université de Montréal
Mathieu Coutu, Université de Montréal
Halima Medjahed, Université de Montréal
Beatriz Pacheco, Harvard Medical School
Alon Herschhorn, Harvard Medical School
Christopher Gu, Harvard Medical School
Shi-Hua Xiang, University of Nebraska-LincolnFollow
Youdong Mao, Harvard Medical School
Joseph Sodroski, Harvard Medical SchoolFollow
Andrés Finzi, Université de MontréalFollow

Document Type

Article

Date of this Version

2013

Citation

Journal of Virology p. 2549–2562 March 2013 Volume 87 Number 5

Comments

Copyright © 2013, American Society for Microbiology. All Rights Reserved.

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.