Structure of the Myristylated Human Immunodeficiency Virus Type 2 Matrix Protein and the Role of Phosphatidylinositol-(4,5)-Bisphosphate in Membrane Targeting

• Published in: Journal of molecular biology Vol. 382; no. 2; pp. 434 - 447
• Main Authors: Saad, Jamil S., Ablan, Sherimay D., Ghanam, Ruba H., Kim, Andrew, Andrews, Kalola, Nagashima, Kunio, Soheilian, Ferri, Freed, Eric O., Summers, Michael F.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 03.10.2008
• Subjects: Animals; Cell Membrane - chemistry; Cell Membrane - metabolism; Gag; HIV-1, HIV-2; HIV-2 - chemistry; HIV-2 - physiology; Human immunodeficiency virus 1; Human immunodeficiency virus 2; Humans; matrix; Models, Molecular; myr; Myristates - chemistry; myristyl; Nuclear Magnetic Resonance, Biomolecular; Phosphatidylinositol 4,5-Diphosphate - chemistry; phosphatidylinositol-4,5-bisphosphate; PI(4,5)P 2; Protein Conformation; Viral Proteins - chemistry; Viral Proteins - metabolism; Virus Replication; HIV-2 Gag; SIV; phosphatidylinositol-4,5-bisphosphate; myr; EM; Gag; matrix; HIV-1, HIV-2; myristyl; 5ptaseIV; RDC; SIV SMM; 2D; HIV; HIV-2 MA; myr(−); NOESY; PI(4,5)P 2; HSQC; myr(+); PM; Ig
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2008.07.027

During the late phase of retroviral replication, newly synthesized Gag proteins are targeted to the plasma membrane (PM), where they assemble and bud to form immature virus particles. Membrane targeting by human immunodeficiency virus type 1 (HIV-1) Gag is mediated by the PM marker molecule phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P 2], which is capable of binding to the matrix (MA) domain of Gag in an extended lipid conformation and of triggering myristate exposure. Here, we show that, as observed previously for HIV-1 MA, the myristyl group of HIV-2 MA is partially sequestered within a narrow hydrophobic tunnel formed by side chains of helices 1, 2, 3, and 5. However, the myristate of HIV-2 MA is more tightly sequestered than that of the HIV-1 protein and does not exhibit concentration-dependent exposure. Soluble PI(4,5)P 2 analogs containing truncated acyl chains bind HIV-2 MA and induce minor long-range structural changes but do not trigger myristate exposure. Despite these differences, the site of HIV-2 assembly in vivo can be manipulated by enzymes that regulate PI(4,5)P 2 localization. Our findings indicate that HIV-1 and HIV-2 are both targeted to the PM for assembly via a PI(4,5)P 2-dependent mechanism, despite differences in the sensitivity of the MA myristyl switch, and suggest a potential mechanism that may contribute to the poor replication kinetics of HIV-2.