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J. Biol. Chem., Vol. 280, Issue 21, 20483-20492, May 27, 2005

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Molecular Determinants of TRIF Proteolysis Mediated by the Hepatitis C Virus NS3/4A Protease^*

Josephine C. Ferreon¶, Allan Chris M. Ferreon||**, Kui Li, and Stanley M. Lemon¶¶

From the Departments of Microbiology and Immunology, and ^||Human Biological Chemistry and Genetics, Center for Hepatitis Research, Institute for Human Infections and Immunity, and ^**Sealy Center for Structural Biology, University of Texas Medical Branch at Galveston, Galveston, Texas 77555-1019

Persistent infections with hepatitis C virus (HCV) are a major cause of liver disease and reflect its ability to disrupt virus-induced signaling pathways activating cellular antiviral defenses. HCV evasion of double-stranded RNA signaling through Toll-like receptor 3 is mediated by the viral protease NS3/4A, which directs proteolysis of its proline-rich adaptor protein, Toll-IL-1 receptor domain containing adaptor-inducing interferon- (TRIF). The TRIF cleavage site has remarkable homology with the viral NS4B/5A substrate, although an 8-residue polyproline track extends upstream from the P₆ position in lieu of the acidic residue present in viral substrates. Circular dichroism (CD) spectroscopy confirmed that a substantial fraction of TRIF exists as polyproline II helices, and inclusion of the polyproline track increased affinity of P side TRIF peptides for the HCV-BK protease. A polyproline II peptide representing an SH3 binding motif (PPPVPPRRR, Sos) bound NS3 with moderate affinity, resulting in inhibition of proteolytic activity. Chemical shift perturbations in NMR spectra indicated that Sos binds a 3₁₀ helix close to the protease active site. Thus, a polyproline II interaction with the 3₁₀ helix likely facilitates NS3/4A recognition of TRIF, indicating a significant difference from NS3/4A recognition of viral substrates. Because SH3 binding motifs are also present in NS5A, a viral protein that interacts with NS3, we speculate that the NS3 3₁₀ helix may be a site of interaction with other viral proteins.

Received for publication, January 12, 2005 , and in revised form, February 28, 2005.

^* This work was supported in part by National Institutes of Health Grants U19-AI40035 and R21-DA018054. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Supported by the James W. McLaughlin Endowment.

Recipient of a Sealy Center for Structural Biology predoctoral fellowship.

John Mitchell Hemophilia of Georgia Liver Scholar of the American Liver Foundation.

^¶¶ To whom correspondence should be addressed: Institute for Human Infections and Immunity, 5.220 Mary Moody Northen Pavilion, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-0428. Tel.: 409-747-6500; Fax: 409-747-6514; E-mail: smlemon{at}utmb.edu.

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