Stoichiometry of HIV-1 Envelope Glycoprotein Protomers with Changes That Stabilize or Destabilize the Pretriggered Conformation.

Autor: Zhang Z; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.; Department of Microbiology, Harvard Medical School, Boston, Massachusetts 02115, USA., Anang S; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.; Department of Microbiology, Harvard Medical School, Boston, Massachusetts 02115, USA., Wang Q; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.; Department of Microbiology, Harvard Medical School, Boston, Massachusetts 02115, USA.; Present address., Nguyen HT; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.; Department of Microbiology, Harvard Medical School, Boston, Massachusetts 02115, USA., Chen HC; Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA., Chiu TJ; Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA., Yang D; Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA., Smith AB 3rd; Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA., Sodroski JG; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.; Department of Microbiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2024 Oct 25. Date of Electronic Publication: 2024 Oct 25.
DOI: 10.1101/2024.10.25.620268
Abstrakt: During human immunodeficiency virus (HIV-1) entry into host cells, binding to the receptors, CD4 and CCR5/CXCR4, triggers conformational changes in the metastable envelope glycoprotein (Env) trimer ((gp120-gp41) 3 ). CD4 binding induces Env to make transitions from its pretriggered conformation (PTC) to more "open" conformations that are sensitive to inhibition by antibodies, CD4-mimetic compounds (CD4mcs) and exposure to cold. Changes in functional membrane Envs have been identified that either stabilize or destabilize the PTC. Here, we investigate the stoichiometric requirements for the PTC-stabilizing and -destabilizing changes in the Env protomers. To this end, we generated viruses bearing Envs with mixed protomers exhibiting different degrees of PTC stability and determined the sensitivity of the viruses to cold (0°C) and, in some cases, to a CD4mc. The number of stabilized Env protomers required to achieve stabilization of the PTC was inversely related to the degree of PTC stabilization that resulted from the introduced Env change. For strongly stabilizing Env changes, modification of a single protomer was sufficient to achieve PTC stabilization; given adequate stability, the modified protomer can apparently constrain the conformation of the other two protomers to maintain the PTC. Weakly stabilizing Env changes needed to be present in all three protomers to achieve efficient stabilization of the PTC. In many cases, the PTC was disrupted when destabilizing changes were present in only a single protomer. These complementary results suggest that conformational symmetry among the protomers of the functional Env trimer is conducive to the integrity of the PTC.
Competing Interests: We declare no conflicts of interest.
Databáze: MEDLINE
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