Cyclopentenone prostaglandin-induced unfolding and aggregation of the Parkinson disease-associated UCH-L1.
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.
Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
Leonardus M I
LM
Koharudin
Hao
H
Liu
Roberto
R
Di Maio
Ravindra B
RB
Kodali
Steven H
SH
Graham
Angela M
AM
Gronenborn
D000818:Animals; D003517:Cyclopentanes / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D009154:Mutation; D010300:Parkinson Disease / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000737:chemistry; D011489:Protein Denaturation; D051381:Rats; D017207:Rats, Sprague-Dawley; D043222:Ubiquitin Thiolesterase / Q000737:chemistry*
D003517:Cyclopentanes; D015230:Prostaglandin D2; D043222:Ubiquitin Thiolesterase; C477819:15-deoxyprostaglandin J2; C507533:Ubiquitin carboxyl-Terminal Hydrolase L-1, human; C489034:UCHL1 protein, rat; C013905:cyclopentenone; C496976:Uchl1 protein, mouse