NMR Structure of the Myristylated Feline Immunodeficiency Virus Matrix Protein |
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Authors: | Lola A. Brown Cassiah Cox Janae Baptiste Holly Summers Ryan Button Kennedy Bahlow Vaughn Spurrier Jenna Kyser Benjamin G. Luttge Lillian Kuo Eric O. Freed Michael F. Summers |
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Affiliation: | 1.Howard Hughes Medical Institute, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA; E-Mails: (L.A.B.); (C.C.); (J.B.); (H.S.); (R.B.); (K.B.); (V.S.); (J.K.);2.Virus-Cell Interaction Section, HIV Drug Resistance Program, National Cancer Institute at Frederick, Frederick, MD 21702-1201, USA; E-Mails: (B.G.L.); (L.K.) |
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Abstract: | Membrane targeting by the Gag proteins of the human immunodeficiency viruses (HIV types-1 and -2) is mediated by Gag’s N-terminally myristylated matrix (MA) domain and is dependent on cellular phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2]. To determine if other lentiviruses employ a similar membrane targeting mechanism, we initiated studies of the feline immunodeficiency virus (FIV), a widespread feline pathogen with potential utility for development of human therapeutics. Bacterial co-translational myristylation was facilitated by mutation of two amino acids near the amino-terminus of the protein (Q5A/G6S; myrMAQ5A/G6S). These substitutions did not affect virus assembly or release from transfected cells. NMR studies revealed that the myristyl group is buried within a hydrophobic pocket in a manner that is structurally similar to that observed for the myristylated HIV-1 protein. Comparisons with a recent crystal structure of the unmyristylated FIV protein [myr(-)MA] indicate that only small changes in helix orientation are required to accommodate the sequestered myr group. Depletion of PI(4,5)P2 from the plasma membrane of FIV-infected CRFK cells inhibited production of FIV particles, indicating that, like HIV, FIV hijacks the PI(4,5)P2 cellular signaling system to direct intracellular Gag trafficking during virus assembly. |
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Keywords: | Feline immunodeficiency virus (FIV) nuclear magnetic resonance (NMR) protein structure retrovirus assembly membrane targeting phosphatidylinositol-4 5-bisphosphate [PI(4 5)-P2 PIP2] |
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