Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 30, Pages 11364-11369Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0602818103
Keywords
matrix protein; membrane targeting; NMR; lipid rafts
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Funding
- NIAID NIH HHS [R37 AI030917, AI30917] Funding Source: Medline
- NIGMS NIH HHS [T34 GM008663, GM08663] Funding Source: Medline
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During the late phase of HIV type 1 (HIV-1) replication, newly synthesized retroviral Gag proteins are targeted to the plasma membrane of most hematopoietic cell types, where they colocalize at lipid rafts and assemble into immature virions. Membrane binding is mediated by the matrix (MA) domain of Gag, a 132-residue polypeptide containing an N-terminal myristyl group that can adopt sequestered and exposed conformations. Although exposure is known to promote membrane binding, the mechanism by which Gag is targeted to specific membranes has yet to be established. Recent studies have shown that phosphaticylinositol (PI) 4,5-bisphosphate [Pl(45)P-2], a factor that regulates localization of cellular proteins to the plasma membrane, also regulates Gag localization and assembly [Ono, A., Ablan, S. D., Lockett, S.J., Nagashima, K. & Freed, E. O. (2004) Proc. Natl. Acad Sci. USA 101, 14889-14894]. Here we show that Pl(4,5)P2 binds directly to HIV-1 MA, inducing a conformational change that triggers myristate exposure. Related phosphatidylinositides PI, PI(3)P, PI(4)P, PI(S)P, and PI(3,5)P2 do not bind MA with significant affinity or trigger myristate exposure. Structural studies reveal that PI(4,5)P2 adopts an extended lipid conformation, in which the inositol head group and 2'-fatty acid chain bind to a hydrophobic cleft, and the 1'-fatty acid and exposed myristyl group bracket a conserved basic surface patch previously implicated in membrane binding. Our findings indicate that PI(4,5)P2 acts as both a trigger of the myristyl switch and a membrane anchor and suggest a potential mechanism for targeting Gag to membrane rafts.
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