Structural basis for conformational plasticity of the Parkinson's disease-associated ubiquitin hydrolase UCH-L1.

TitleStructural basis for conformational plasticity of the Parkinson's disease-associated ubiquitin hydrolase UCH-L1.
Publication TypeJournal Article
Year of Publication2006
AuthorsDas C, Hoang QQ, Kreinbring CA, Luchansky SJ, Meray RK, Ray SS, Lansbury PT, Ringe D, Petsko GA
JournalProc Natl Acad Sci U S A
Date Published2006 Mar 21
KeywordsAmino Acid Sequence, Binding Sites, Crystallography, X-Ray, Dimerization, Humans, Models, Biological, Molecular Sequence Data, Parkinson Disease, Protein Conformation, Ubiquitin Thiolesterase

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-A 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.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID16537382
PubMed Central IDPMC1450230
Grant ListCO-1020 / CO / NCI NIH HHS / United States
GM-1104 / GM / NIGMS NIH HHS / United States