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TitleThe conserved HIV-1 spacer peptide 2 triggers matrix lattice maturation.
Journal, issue, pagesbioRxiv, Year 2024
Publish dateNov 6, 2024
AuthorsJames C V Stacey / Dominik Hrebík / Elizabeth Nand / Snehith Dyavari Shetty / Kun Qu / Marius Boicu / Maria Anders-Össwein / Robert A Dick / Walther Mothes / Hans-Georg Kräusslich / Barbara Müller / John A G Briggs /
PubMed AbstractHIV-1 particles are released in an immature, non-infectious form. Proteolytic cleavage of the main structural polyprotein Gag into functional domains induces rearrangement into mature, infectious ...HIV-1 particles are released in an immature, non-infectious form. Proteolytic cleavage of the main structural polyprotein Gag into functional domains induces rearrangement into mature, infectious virions. In immature virus particles, the Gag membrane binding domain, MA, forms a hexameric protein lattice that undergoes structural transition upon cleavage into a distinct, mature MA lattice. The mechanism of MA lattice maturation is unknown. Here we show that released spacer peptide 2 (SP2), a conserved peptide of unknown function situated ~300 residues downstream of MA, binds MA to induce structural maturation. By high-resolution in-virus structure determination of MA, we show that MA does not bind lipid into a side pocket as previously thought, but instead binds SP2 as an integral part of the protein-protein interfaces that stabilise the mature lattice. Analysis of Gag cleavage site mutants showed that SP2 release is required for MA maturation, and we demonstrate that SP2 is sufficient to induce maturation of purified MA on lipid layers in vitro. SP2-triggered MA maturation correlated with faster fusion of virus with target cells. Our results reveal a new, unexpected interaction between two HIV-1 components, provide a high-resolution structure of mature MA, establish the trigger of MA structural maturation, and assign function to the SP2 peptide.
External linksbioRxiv / PubMed:39574591 / PubMed Central
MethodsEM (single particle)
Resolution3.41 - 3.83 Å
Structure data

EMDB-52221: Mature HIV-1 matrix from WT virus particle
Method: EM (single particle) / Resolution: 3.83 Å

EMDB-52222: Mature HIV-1 matrix from MA-NC cleavage mutant
Method: EM (single particle) / Resolution: 3.41 Å

Source
  • Human immunodeficiency virus 1

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