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spinqualitylabelsall models 2f1x, resolution 2.3Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal structure of the TRAF-like domain of HAUSP/USP7 bound to a p53 peptide

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Herpesvirus-associated ubiquitin-specific protease (HAUSP, also known as, USP7), a deubiquitylating enzyme of the ubiquitin-specific processing, protease family, specifically deubiquitylates both p53 and MDM2, hence, playing an important yet enigmatic role in the p53-MDM2 pathway. Here we, demonstrate that both p53 and MDM2 specifically recognize the N-terminal, tumor necrosis factor-receptor associated factor (TRAF)-like domain of, HAUSP in a mutually exclusive manner. HAUSP preferentially forms a stable, HAUSP-MDM2 complex even in the presence of excess p53. The HAUSP-binding, elements were mapped to a peptide fragment in the carboxy-terminus of p53, and to a short-peptide region preceding the acidic domain of MDM2. The, crystal structures of the HAUSP TRAF-like domain in complex with p53 and, MDM2 peptides, determined at 2.3-A and 1.7-A resolutions, respectively, reveal that the MDM2 peptide recognizes the same surface groove in HAUSP, as that recognized by p53 but mediates more extensive interactions., Structural comparison led to the identification of a consensus, peptide-recognition sequence by HAUSP. These results, together with the, structure of a combined substrate-binding-and-deubiquitylation domain of, HAUSP, provide important insights into regulation of the p53-MDM2 pathway, by HAUSP.

Disease

Known diseases associated with this structure: Adrenal cortical carcinoma OMIM:[191170], Breast cancer OMIM:[191170], Colorectal cancer OMIM:[191170], Hepatocellular carcinoma OMIM:[191170], Histiocytoma OMIM:[191170], Li-Fraumeni syndrome OMIM:[191170], Multiple malignancy syndrome OMIM:[191170], Nasopharyngeal carcinoma OMIM:[191170], Osteosarcoma OMIM:[191170], Pancreatic cancer OMIM:[191170], Thyroid carcinoma OMIM:[191170]

About this Structure

2F1X is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Structural basis of competitive recognition of p53 and MDM2 by HAUSP/USP7: implications for the regulation of the p53-MDM2 pathway., Hu M, Gu L, Li M, Jeffrey PD, Gu W, Shi Y, PLoS Biol. 2006 Feb;4(2):e27. Epub 2006 Jan 17. PMID:16402859

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