2XXN

Structure of the vIRF4-HAUSP TRAF domain complex

Summary for 2XXN

• Entry DOI: 10.2210/pdb2xxn/pdb
• Related: 1NB8 1NBF 2F1W 2F1X 2F1Y 2F1Z 2FOJ 2FOO 2FOP
• Descriptor: UBIQUITIN CARBOXYL-TERMINAL HYDROLASE 7, K10 (3 entities in total)
• Functional Keywords: hydrolase, kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor 4
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Nucleus: Q93009
• Total number of polymer chains: 2
• Total formula weight: 18349.53

Authors

Choi, W.C.,Hwang, J.,Kim, M.H. (deposition date: 2010-11-11, release date: 2011-11-09, Last modification date: 2023-12-20)

Primary citation

Lee, H.R.,Choi, W.C.,Lee, S.,Hwang, J.,Hwang, E.,Guchhait, K.,Haas, J.,Toth, Z.,Jeon, Y.H.,Oh, T.K.,Kim, M.H.,Jung, J.U.
Bilateral Inhibition of Hausp Deubiquitinase by a Viral Interferon Regulatory Factor Protein
Nat.Struct.Mol.Biol., 18:1336-, 2011

PubMed Abstract: Herpesvirus-associated ubiquitin-specific protease (HAUSP) regulates the stability of p53 and the p53-binding protein MDM2, implicating HAUSP as a therapeutic target for tuning p53-mediated antitumor activity. Here we report the structural analysis of HAUSP with Kaposi's sarcoma-associated herpesvirus viral interferon (IFN) regulatory factor 4 (vIRF4) and the discovery of two vIRF4-derived peptides, vif1 and vif2, as potent and selective HAUSP antagonists. This analysis reveals a bilateral belt-type interaction that results in inhibition of HAUSP. The vif1 peptide binds the HAUSP TRAF domain, competitively blocking substrate binding, whereas the vif2 peptide binds both the HAUSP TRAF and catalytic domains, robustly suppressing its deubiquitination activity. Peptide treatments comprehensively blocked HAUSP, leading to p53-dependent cell-cycle arrest and apoptosis in culture and to tumor regression in xenograft mouse model. Thus, the virus has developed a unique strategy to target the HAUSP-MDM2-p53 pathway, and these virus-derived short peptides represent biologically active HAUSP antagonists.

PubMed: 22056774
DOI: 10.1038/NSMB.2142

Experimental method

X-RAY DIFFRACTION (1.6 Å)