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.
Aisenbrey
Christopher
C
Institut/Faculté de Chimie, Université Louis Pasteur/CNRS LC3-Unité Mixte de Recherche 7177, 4 Rue Blaise Pascal, Strasbourg 67070, France.
Sizun
Christina
C
Koch
Joachim
J
Herget
Meike
M
Abele
Rupert
R
Bechinger
Burkhard
B
Tampé
Robert
R
D002462:Cell Membrane / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D017874:Immediate-Early Proteins / Q000737:chemistry*; D008051:Lipid Bilayers / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008285:Major Histocompatibility Complex; D008958:Models, Molecular; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011522:Protons; D018139:Simplexvirus / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000821:virology; D013696:Temperature; D014764:Viral Proteins / Q000737:chemistry*
C105843:ICP47 protein, Herpes simplex virus; D017874:Immediate-Early Proteins; D008051:Lipid Bilayers; D011522:Protons; D014764:Viral Proteins