Site-specific, intramolecular cross-linking of Pin1 active site residues by the lipid electrophile 4-oxo-2-nonenal

Chemical Research in Toxicology
Christopher D AluiseLawrence J Marnett

Abstract

Products of oxidative damage to lipids include 4-hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE), both of which are cytotoxic electrophiles. ONE reacts more rapidly with nucleophilic amino acid side chains, resulting in covalent protein adducts, including residue-residue cross-links. Previously, we demonstrated that peptidylprolyl cis/trans isomerase A1 (Pin1) was highly susceptible to adduction by HNE and that the catalytic cysteine (Cys113) was the preferential site of modification. Here, we show that ONE also preferentially adducts Pin1 at the catalytic Cys but results in a profoundly different modification. Results from experiments using purified Pin1 incubated with ONE revealed the principal product to be a Cys-Lys pyrrole-containing cross-link between the side chains of Cys113 and Lys117. In vitro competition assays between HNE and ONE demonstrate that ONE reacts more rapidly than HNE with Cys113. Exposure of RKO cells to alkynyl-ONE (aONE) followed by copper-mediated click chemistry and streptavidin purification revealed that Pin1 is also modified by ONE in cells. Analysis of the Pin1 crystal structure reveals that Cys113 and Lys117 are oriented toward each other in the active site, facilitating formation of an ONE cro...Continue Reading

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Citations

Dec 2, 2015·Current Opinion in Chemical Biology·Ying ChenChu Wang
Jun 15, 2015·Redox Biology·Giancarlo AldiniDolores Pérez-Sala
Sep 12, 2015·Chemical Research in Toxicology·Venkataraman Amarnath, Kalyani Amarnath
Aug 31, 2016·Archives of Pharmacal Research·Sang-Hyun MinKun Ping Lu
Dec 17, 2016·Chemical Research in Toxicology·Jeannie M CamarilloLawrence J Marnett
Aug 18, 2017·Molecular & Cellular Proteomics : MCP·Rui SunJing Yang
Dec 24, 2019·Essays in Biochemistry·Corinne M Spickett, Andrew R Pitt
Mar 7, 2021·Antioxidants·Álvaro Viedma-PoyatosDolores Pérez-Sala

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Software Mentioned

ONE
Scaffold
Xcalibur
FlexAnalysis
Sequest
Protein Prospector
Proteome

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