期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 103, 期 12, 页码 4675-4680出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0510403103
关键词
neurodegeneration; ubiquitination; ubiquitin ligase; x-ray crystallography
资金
- NCI NIH HHS [CO-1020] Funding Source: Medline
- NIGMS NIH HHS [GM-1104] Funding Source: Medline
The ubiquitin C-terminal hydrolase UCH-L1 (PGP9.5) comprises > 1% of total brain protein but is almost absent from other tissues [Wilkinson, K. D., et al. (1989) Science 246,670-673]. Mutations in the UCH-L1 gene have been reported to be linked to susceptibility to and protection from Parkinson's disease [Leroy, E., et al. (1998) Nature 395, 451-452; Maraganore, D. M., et al. (1999) Neurology 53, 1858-1860]. Abnormal overexpression of UCH-L1 has been shown to correlate with several forms of cancer [Hibi, K., et al. (1998) Cancer Res. 58, 5690-5694]. Because the amino acid sequence of UCH-L1 is similar to that of other ubiquitin C-terminal hydrolases, including the ubiquitously expressed UCH-L3, which appear to be unconnected to neurodegenerative disease, the structure of UCH-L1 and the effects of disease associated mutations on the structure and function are of considerable importance. We have determined the three-dimensional structure of human UCH-L1 at 2.4-angstrom resolution by x-ray crystallography. The overall fold resembles that of other ubiquitin hydrolases, including UCH-L3, but there are a number of significant differences. In particular, the geometry of the catalytic residues in the active site of UCH-L1 is distorted in such a way that the hydrolytic activity would appear to be impossible without substrate induced conformational rearrangements.
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