Inositol phosphates are assembly co-factors for HIV-1

Dick, Robert A.; Zadrozny, Kaneil K.; Xu, Chaoyi; Schur, Florian K. M.; Lyddon, Terri D.; Ricana, Clifton L.; Wagner, Jonathan M.; Perilla, Juan R.; Ganser-Pornillos, Barbie K.; Johnson, Marc C.; Pornillos, Owen; Vogt, Volker M.

doi:10.1038/s41586-018-0396-4

Title: Inositol phosphates are assembly co-factors for HIV-1

Journal Article · Wed Aug 01 00:00:00 EDT 2018 · Nature (London)

DOI:https://doi.org/10.1038/s41586-018-0396-4· OSTI ID:1474170

Dick, Robert A. ^[1]; Zadrozny, Kaneil K. ^[2]; Xu, Chaoyi ^[3]; Schur, Florian K. M. ^[4]; Lyddon, Terri D. ^[5]; Ricana, Clifton L. ^[5]; Wagner, Jonathan M. ^[2]; Perilla, Juan R. ^[3]; Ganser-Pornillos, Barbie K. ^[2]; Johnson, Marc C. ^[5]; Pornillos, Owen ^[2]; Vogt, Volker M. ^[1]

Cornell Univ., Ithaca, NY (United States)
Univ. of Virginia, Charlottesville, VA (United States)
Univ. of Delaware, Newport, DE (United States)
EMBL, Heidelberg (Germany); Inst. of Science and Technology Austria, Klosterneuburg (Austria)
Univ. of Missouri, Columbia, MO (United States)

A short, 14-amino-acid segment called SP1, located in the Gag structural protein, has a critical role during the formation of the HIV-1 virus particle. During virus assembly, the SP1 peptide and seven preceding residues fold into a six-helix bundle, which holds together the Gag hexamer and facilitates the formation of a curved immature hexagonal lattice underneath the viral membrane. Upon completion of assembly and budding, proteolytic cleavage of Gag leads to virus maturation, in which the immature lattice is broken down; the liberated CA domain of Gag then re-assembles into the mature conical capsid that encloses the viral genome and associated enzymes. Folding and proteolysis of the six-helix bundle are crucial rate-limiting steps of both Gag assembly and disassembly, and the six-helix bundle is an established target of HIV-1 inhibitors. Here, using a combination of structural and functional analyses, we show that inositol hexakisphosphate (InsP6, also known as IP₆) facilitates the formation of the six-helix bundle and assembly of the immature HIV-1 Gag lattice. IP₆ makes ionic contacts with two rings of lysine residues at the centre of the Gag hexamer. Proteolytic cleavage then unmasks an alternative binding site, where IP₆ interaction promotes the assembly of the mature capsid lattice. Furthermore, these studies identify IP6 as a naturally occurring small molecule that promotes both assembly and maturation of HIV-1.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Inst. of Health; German Research Foundation (DFG); National Science Foundation (NSF)

Grant/Contract Number:: R01-GM116961; OCI-1053575; ACI-1445606; R01-GM107013; R01-GM105684; P30-GM110758; P50-GM082251; R01-AI129678; U54-GM103297; R01-GM110776; BR 3635/2-1

OSTI ID:: 1474170

Journal Information:: Nature (London), Vol. 560, Issue 7719; ISSN 0028-0836

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 109 works

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