Mechanisms of PI(4,5)P2 Enrichment in HIV-1 Viral Membranes.
giant unilamellar vesicle
human immunodeficiency virus
large unilamellar vesicle
matrix protein
myristoylation
Journal
Journal of molecular biology
ISSN: 1089-8638
Titre abrégé: J Mol Biol
Pays: Netherlands
ID NLM: 2985088R
Informations de publication
Date de publication:
04 09 2020
04 09 2020
Historique:
received:
01
06
2020
revised:
12
07
2020
accepted:
26
07
2020
pubmed:
3
8
2020
medline:
10
3
2021
entrez:
3
8
2020
Statut:
ppublish
Résumé
Phosphatidylinositol 4,5-bisphosphate (PIP2) is critical for HIV-1 virus assembly. The viral membrane is enriched in PIP2, suggesting that the virus assembles at PIP2-rich microdomains. We showed previously that in model membranes PIP2 can form nanoscopic clusters bridged by multivalent cations. Here, using purified proteins we quantitated the binding of HIV-1 Gag-related proteins to giant unilamellar vesicles containing either clustered or free PIP2. Myristoylated MA strongly preferred binding to clustered PIP2. By contrast, unmyristoylated HIV-1 MA, RSV MA, and a PH domain all preferred to interact with free PIP2. We also found that HIV-1 Gag multimerization promotes PIP2 clustering. Truncated Gag proteins comprising the MA, CA, and SP domains (MACASP) or the MA and CA domains (MACA) induced self-quenching of acyl chain-labeled fluorescent PIP2 in liposomes, implying clustering. However, HIV-1 MA itself did not induce PIP2 clustering. A CA inter-hexamer dimer interface mutation led to a loss of induced PIP2 clustering in MACA, indicating the importance of protein multimerization. Cryo-electron tomography of liposomes with bound MACA showed an amorphous protein layer on the membrane surface. Thus, it appears that while protein-protein interactions are required for PIP2 clustering, formation of a regular lattice is not. Protein-induced PIP2 clustering and multivalent cation-induced PIP2 clustering are additive. Taken together, these results provide the first evidence that HIV-1 Gag can selectively target pre-existing PIP2-enriched domains of the plasma membrane for viral assembly, and that Gag multimerization can further enrich PIP2 at assembly sites. These effects could explain the observed PIP2 enrichment in HIV-1.
Identifiants
pubmed: 32739462
pii: S0022-2836(20)30473-3
doi: 10.1016/j.jmb.2020.07.018
pmc: PMC8262684
mid: NIHMS1717033
pii:
doi:
Substances chimiques
Phosphatidylinositol 4,5-Diphosphate
0
Unilamellar Liposomes
0
gag Gene Products, Human Immunodeficiency Virus
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
5343-5364Subventions
Organisme : NIAID NIH HHS
ID : R01 AI147890
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI150454
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM105684
Pays : United States
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.
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