1q02

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NMR structure of the UBA domain of p62 (SQSTM1)

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

The p62 protein (also known as SQSTM1) mediates diverse cellular functions, including control of NFkappaB signaling and transcriptional activation., p62 binds non-covalently to ubiquitin and co-localizes with ubiquitylated, inclusions in a number of human protein aggregation diseases. Mutations in, the gene encoding p62 cause Paget's disease of bone (PDB), a common, disorder of the elderly characterized by excessive bone resorption and, formation. All of the p62 PDB mutations identified to date cluster within, the C-terminal region of the protein, which shows low sequence identity to, previously characterized ubiquitin-associated (UBA) domains. We report the, first NMR structure of a recombinant polypeptide that contains the, C-terminal UBA domain of the human p62 protein (residues 387-436). This, sequence, which confers multiubiquitin chain binding, forms a compact, three-helix bundle with a structure analogous to the UBA domains of HHR23A, but with differences in the loop regions connecting helices that may be, involved in binding accessory proteins. We show that the Pro392 --> Leu, PDB substitution mutation modifies the structure of the UBA domain by, extending the N terminus of helix 1. In contrast to the p62 PDB deletion, mutations that remove the UBA domain and ablate multiubiquitin chain, binding, the Pro392 --> Leu substitution does not affect interaction of, the UBA domain with multiubiquitin chains. Thus, phenotypically identical, substitution and deletion mutations do not appear to predispose to PDB, through a mechanism dependent on a common loss of ubiquitin chain binding, by p62.

Disease

Known disease associated with this structure: Paget disease of bone OMIM:[601530]

About this Structure

1Q02 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Structure of the ubiquitin-associated domain of p62 (SQSTM1) and implications for mutations that cause Paget's disease of bone., Ciani B, Layfield R, Cavey JR, Sheppard PW, Searle MS, J Biol Chem. 2003 Sep 26;278(39):37409-12. Epub 2003 Jul 11. PMID:12857745

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