Portal de Periódicos da CAPES

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

2006; National Academy of Sciences; Volume: 103; Issue: 12 Linguagem: Inglês

10.1073/pnas.0510403103

1091-6490

Chittaranjan Das, Quyen Q. Hoang, C.A. Kreinbring, Sarah J. Luchansky, Robin K. Meray, Soumya S. Ray, Peter T. Lansbury, Dagmar Ringe, Gregory A. Petsko,

Genetics and Neurodevelopmental Disorders

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-Å 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.