Structure and dynamics of membrane-associated ICP47, a viral inhibitor of the MHC I antigen-processing machinery

• 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.

Nyckelord

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

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)