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Structure of the viral TAP-inhibitor ICP47 induced by membrane association

D Beinert1, L Neumann, S Uebel

  • 1Max-Planck-Institut für Biochemie, Martinsried, Germany.

Biochemistry
|April 15, 1997
PubMed

Insights

Herpes simplex virus protein ICP47 inhibits antigen presentation by blocking the transporter associated with antigen processing (TAP). Membrane binding induces a structural change in ICP47, which is crucial for inhibiting TAP function.

Area of Science:

  • Virology
  • Immunology
  • Structural Biology

Background:

  • Herpes simplex virus type I protein ICP47 (IE12) inhibits antigen presentation.
  • ICP47 blocks the transporter associated with antigen processing (TAP), preventing MHC class I assembly and cell surface presentation.
  • This mechanism hinders immune recognition by cytotoxic T-lymphocytes.

Purpose of the Study:

  • Investigate the structure of ICP47, the first natural inhibitor of an ATP-binding-cassette (ABC) transporter.
  • Determine the functional N-terminal half of ICP47 as a model for studying its inhibitory mechanism.
  • Elucidate the role of membrane interactions in ICP47's conformational changes and TAP inhibition.

Main Methods:

  • Circular dichroism (CD) spectroscopy to analyze protein structure in solution and in the presence of membrane mimetics.
  • Fluorescence spectroscopy to study protein-membrane interactions.
  • Biochemical assays to assess TAP inhibition by ICP47 and its variants.

Main Results:

  • The N-terminal half of ICP47 exhibits full inhibitory activity against human TAP.
  • ICP47 is unstructured in aqueous solution but adopts an alpha-helical structure upon interaction with lipid membranes.
  • Membrane adsorption and conformational changes are dependent on lipid membrane surface charge density.

Conclusions:

  • ICP47's N-terminal region is sufficient for TAP inhibition.
  • Membrane docking induces a critical conformational change in ICP47.
  • This membrane-induced structural alteration is likely a prerequisite for blocking TAP transporter function.

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