Topological Layers in the HIV-1 gp120 Inner Domain Regulate gp41 Interaction and CD4-Triggered Conformational Transitions

Andrés Finzi, Shi Hua Xiang, Beatriz Pacheco, Liping Wang, Jessica Haight, Aemro Kassa, Brenda Danek, Marie Pancera, Peter D. Kwong, Joseph Sodroski

Research output: Contribution to journalArticlepeer-review

138 Scopus citations

Abstract

The entry of human immunodeficiency virus (HIV-1) into cells is initiated by binding of the gp120 exterior envelope glycoprotein to the receptor, CD4. How does CD4 binding trigger conformational changes in gp120 that allow the gp41 transmembrane envelope glycoprotein to mediate viral-cell membrane fusion? The transition from the unliganded to the CD4-bound state is regulated by two potentially flexible topological layers (layers 1 and 2) in the gp120 inner domain. Both layers apparently contribute to the noncovalent association of unliganded gp120 with gp41. After CD4 makes initial contact with the gp120 outer domain, layer 1-layer 2 interactions strengthen gp120-CD4 binding by reducing the off rate. Layer 1-layer 2 interactions also destabilize the activated state induced on HIV-1 by treatment with soluble CD4. Thus, despite lack of contact with CD4, the gp120 inner-domain layers govern CD4 triggering by participating in conformational transitions within gp120 and regulating the interaction with gp41.

Original languageEnglish (US)
Pages (from-to)656-667
Number of pages12
JournalMolecular Cell
Volume37
Issue number5
DOIs
StatePublished - Mar 12 2010

Keywords

  • HUMDISEASE
  • PROTEINS
  • SIGNALING

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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