Loss of ubiquitin binding is a unifying mechanism by which mutations of SQSTM1 cause Paget's disease of bone

被引:67
作者
Cavey, J. R.
Ralston, S. H.
Sheppard, P. W.
Ciani, B.
Gallagher, T. R. A.
Long, J. E.
Searle, M. S.
Layfield, R. [1 ]
机构
[1] Univ Nottingham, Sch Med, Sch Biomed Sci, Nottingham NG7 2UH, England
[2] Univ Edinburgh, Western Gen Hosp, Rheumat Dis Unit, Edinburgh EH2 2XU, Midlothian, Scotland
[3] BIOMOL Int, Exeter EX2 8NL, Devon, England
[4] Ctr Biomol Sci, Sch Chem, Nottingham NG7 2RD, England
基金
英国惠康基金;
关键词
ubiquitin; ubiquitin-associated domain; SQSTM1; p62; Paget's disease of bone;
D O I
10.1007/s00223-005-1299-6
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Ubiquitin-associated (UBA) domain mutations of SQSTM1 are an important cause of Paget's disease of bone (PDB), which is a human skeletal disorder characterized by abnormal bone turnover. We previously showed that, when introduced into the full-length SQSTM1 protein, the disease-causing P392L, M404V, G411S, and G425R missense mutations and the E396X truncating mutation (representative of all of the SQSTM1 truncating mutations) cause a generalized loss of monoubiquitin binding and impaired K48-linked polyubiquitin binding at physiological temperature. Here, we show that the remaining three known PDB missense mutations, P387L, S399P, and M404T, have similar deleterious effects on monoubiquitin binding and K48-linked polyubiquitin binding by SQSTM1. The P387L mutation affects an apparently unstructured region at the N terminus of the UBA domain, some five residues from the start of the first helix, which is dispensable for polyubiquitin binding by the isolated UBA domain. Our findings support the proposal that the disease mechanism in PDB with SQSTM1 mutations involves a common loss of ubiquitin binding function of SQSTM1 and implicate a sequence extrinsic to the compact globular region of the UBA domain as a critical determinant of ubiquitin recognition by the full-length SQSTM1 protein.
引用
收藏
页码:271 / 277
页数:7
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