Oxidation of membrane phospholipids is associated with neurodegeneration, inflammation, and cancer. 4-Hydroxynonenal (HNE), a common product of lipid peroxidation, adducts proteins at exposed Cys, His, or Lys residues and can modulate protein activity. Here, we provide evidence that peptidylprolyl cis/trans isomerase A1 (Pin1), an enzyme that catalyzes the conversion of pSer/pThr-Pro moieties in signaling proteins from cis to trans, is highly susceptible to HNE-modification. Incubation of purified Pin1 with HNE followed by MALDI-TOF/TOF mass spectrometry revealed that the most reactive amino acids are His-157 and Cys-113, both of which are active site residues.  Pin1 was adducted in MDA-MB-231 cells treated with 8-alkynyl-HNE, and knockdown of Pin1 in these cells partially protected the cells from HNE-induced toxicity. Cell lysates treated with HNE displayed decreased prolyl isomerase activity as a function of electrophile concentration.  The present study establishes that Pin1 is a critical target for electrophilic modification by products of lipid peroxidation.

Peptidylprolyl cis/trans isomerase A1 (Pin1) is modified by lipid electrophiles generated during oxidative stress

244th National Meeting (2012)

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