PDBsum entry 1q02

Protein binding

PDB id: 1q02

Contents

Protein chain

52 a.a. *

* Residue conservation analysis

References listed in PDB file

Key reference

Title

Structure of the ubiquitin-Associated domain of p62 (sqstm1) and implications for mutations that cause paget'S disease of bone.

Authors

B.Ciani, R.Layfield, J.R.Cavey, P.W.Sheppard, M.S.Searle.

Ref.

J Biol Chem, 2003, 278, 37409-37412. [DOI no: 10.1074/jbc.M307416200]

PubMed id

12857745

Abstract

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.

Figure 1.
FIG. 1. a, domain structure of the p62 protein and Paget's disease of bone mutation sites (SH2, AID, ZZ, and TRAF6 refer to binding sites for the SH2 domain of p56^lck, aPKC, RIP, and TRAF6, respectively), and b, sequence alignment of the p62-UBA domain with the HHR23A-UBA domains (alignment from SMART data base; see Ref. 7).

Figure 3.
FIG. 3. a, ribbon structure of the p62-UBA domain with key side chains highlighted with MOLMOL (30); b, overlaid backbone of the p62-UBA (light) and UBA (2) of HHR23A (dark) (Protein Data Bank code 1DV0 [PDB] ) showing the helical alignment and differences in loop 1 incorporating Glu409 and Gly410 in p62.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 37409-37412) copyright 2003.