Structural basis for conformational plasticity of the Parkinson's disease-associated ubiquitin hydrolase UCH-L1.
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.
Das
Chittaranjan
C
Department of Chemistry and Biochemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02454-9110, USA.
Hoang
Quyen Q
QQ
Kreinbring
Cheryl A
CA
Luchansky
Sarah J
SJ
Meray
Robin K
RK
Ray
Soumya S
SS
Lansbury
Peter T
PT
Ringe
Dagmar
D
Petsko
Gregory A
GA
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D010300:Parkinson Disease / Q000201:enzymology*; D011487:Protein Conformation; D043222:Ubiquitin Thiolesterase / Q000737:chemistry*
C482860:UCHL1 protein, human; D043222:Ubiquitin Thiolesterase