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Structure and dynamics of membrane-associated ICP47, a viral inhibitor of the MHC I antigen-processing machinery
Umeå University, Faculty of Science and Technology, Chemistry.
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2006 (English)In: The Journal of Biological Chemistry, ISSN 0021-9258, Vol. 281, no 41, 30365-72 p.Article in journal (Refereed) Published
Abstract [en]

To evade the host's immune response, herpes simplex virus employs the immediate early gene product ICP47 (IE12) to suppress antigen presentation to cytotoxic T-lymphocytes by inhibition of the ATP-binding cassette transporter associated with antigen processing (TAP). ICP47 is a membrane-associated protein adopting an alpha-helical conformation. Its active domain was mapped to residues 3-34 and shown to encode all functional properties of the full-length protein. The active domain of ICP47 was reconstituted into oriented phospholipid bilayers and studied by proton-decoupled 15N and 2H solid-state NMR spectroscopy. In phospholipid bilayers, the protein adopts a helix-loop-helix structure, where the average tilt angle of the helices relative to the membrane surface is approximately 15 degrees (+/- 7 degrees ). The alignment of both structured domains exhibits a mosaic spread of approximately 10 degrees . A flexible dynamic loop encompassing residues 17 and 18 separates the two helices. Refinement of the experimental data indicates that helix 1 inserts more deeply into the membrane. These novel insights into the structure of ICP47 represent an important step toward a molecular understanding of the immune evasion mechanism of herpes simplex virus and are instrumental for the design of new therapeutics.

Place, publisher, year, edition, pages
2006. Vol. 281, no 41, 30365-72 p.
Keyword [en]
Cell Membrane/metabolism, Dimerization, Humans, Immediate-Early Proteins/*chemistry, Lipid Bilayers/chemistry, Magnetic Resonance Spectroscopy, Major Histocompatibility Complex, Models; Molecular, Protein Conformation, Protein Structure; Secondary, Protons, Simplexvirus/metabolism, T-Lymphocytes; Cytotoxic/virology, Temperature, Viral Proteins/*chemistry
URN: urn:nbn:se:umu:diva-11081DOI: doi:10.1074/jbc.M603000200PubMedID: 16835230OAI: diva2:150752
Available from: 2008-03-31 Created: 2008-03-31 Last updated: 2011-01-11Bibliographically approved

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