The Effect of Parkinson's-Disease-Associated Mutations on the Deubiquitinating Enzyme UCH-L1
| Autor: | Elizabeth F. Werrell, Sophie E. Jackson, Chittarnajan Das, Shang-Te Danny Hsu, Lindsay M. McMorran, William J. K. Crone, Fredrik Andersson |
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| Rok vydání: | 2011 |
| Předmět: |
Models
Molecular Protein Denaturation Magnetic Resonance Spectroscopy Genotype Mutant medicine.disease_cause Deubiquitinating enzyme Ubiquitin Structural Biology Enzyme Stability Hydrolase medicine Humans Point Mutation Molecular Biology Mutation biology Chemistry Point mutation Autophagy Wild type Deuterium Exchange Measurement Parkinson Disease Molecular biology biology.protein Thermodynamics Hydrophobic and Hydrophilic Interactions Ubiquitin Thiolesterase |
| Zdroj: | Journal of Molecular Biology. 407:261-272 |
| ISSN: | 0022-2836 |
| Popis: | The neuronal ubiquitin C-terminal hydrolase (UCH) UCH-L1 has been linked to Parkinson's disease (PD) and other neurodegenerative diseases. Here, we present a study on the structure, stability, unfolding, and dynamics of wild-type and mutant UCH-L1. Fluorescence, far-UV CD, and NMR measurements were used to establish that the unfolding of UCH-L1 is three-state under equilibrium conditions and that an intermediate is populated. S18Y and I93M mutants, which are associated with a decreased risk or an increased risk of PD, respectively, are less stable than wild type. However, while there is minimal structural perturbation in the S18Y mutant, the I93M mutation is more disruptive. In particular, the NMR data suggest that there are local rearrangements around the site of the mutation, which we propose results in the exposure of hydrophobic surface area. This may have two consequences: an increased tendency towards, firstly, aggregation in vivo, and, secondly, aberrant interactions with tubulin and the chaperone-mediated autophagy machinery as observed by other groups, both of which may be involved in neurodegenerative processes. |
| Databáze: | OpenAIRE |
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