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Cyclopentenone prostaglandin-induced unfolding and aggregation of the Parkinson disease-associated UCH-L1.


ABSTRACT: Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) has been implicated in Parkinson's disease (PD) and is present in neurofibrillary tangles or Lewy bodies. However, the molecular basis for UCH-L1s involvement in proteinacious fibril formation is still elusive, especially in regard to the pathogenicity of the I93M mutation. Here we show that modification of UCH-L1 by cyclopentenone prostaglandins causes unfolding and aggregation. A single thiol group on Cys152 reacts with the alpha,beta-unsaturated carbonyl center in the cyclopentenone ring of prostaglandins, resulting in a covalent adduct. We also show that the PD-associated I93M mutant of UCH-L1 is well-folded, structurally similar to the wild-type protein, and aggregates upon conjugation by cyclopentenone prostaglandins. Our findings suggest a possible mechanistic link between UCH-L1 modification by cyclopentenone prostaglandins and the etiology of neurodegeneration.

SUBMITTER: Koharudin LM 

PROVIDER: S-EPMC2872412 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Cyclopentenone prostaglandin-induced unfolding and aggregation of the Parkinson disease-associated UCH-L1.

Koharudin Leonardus M I LM   Liu Hao H   Di Maio Roberto R   Kodali Ravindra B RB   Graham Steven H SH   Gronenborn Angela M AM  

Proceedings of the National Academy of Sciences of the United States of America 20100315 15


Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) has been implicated in Parkinson's disease (PD) and is present in neurofibrillary tangles or Lewy bodies. However, the molecular basis for UCH-L1s involvement in proteinacious fibril formation is still elusive, especially in regard to the pathogenicity of the I93M mutation. Here we show that modification of UCH-L1 by cyclopentenone prostaglandins causes unfolding and aggregation. A single thiol group on Cys152 reacts with the alpha,beta-unsaturat  ...[more]

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