Lipid electrophile adduction of Pin1 and effects on substrate binding &activity

Summary

Principal Investigator: Christopher D Aluise
Abstract: DESCRIPTION (provided by applicant): Oxidative damage to cellular lipids is a contributing factor to aging, as well as many peripheral and central nervous system diseases. Reactive oxygen species-induced modification of polyunsaturated fatty acids results in the production of electrophilic metabolites capable of irreversibly modifying proteins, carbohydrates, and DNA. Examples of lipid electrophiles that have been extensively studied are 4-hydroxynonenal (4-HNE), 4- oxononenal (4-ONE), acrolein, and malondialdehyde. Adduction by lipid electrophiles distorts protein tertiary structure and typically has adverse effects on protein function. Despite an undeniable connection to aging as well as a multitude of diseases where oxidative stress occurs, the susceptibility of peptidyl-prolyl cis/trans isomerase A1 (Pin1) to adduction by different electrophiles has not been thoroughly investigated. In human colorectal carcinoma cells (RKO), I will map the adduction sites of Pin1 in vitro using proteomics. I will examine the potential downstream effects of 4-HNE and 4-ONE adduction to Pin1 in terms of substrate binding and prolyl isomerization activity. Furthermore, I propose that Pin1 modification by electrophiles results in an inability to catalyze the proline-directed isomerization of several Raf1 moieties necessary for dephosphorylation by protein phosphatase 2A, resulting in prolonged hyperphosphorylation/inactivation. This investigation represents the first study to mechanistically examine electrophile adduction of Pin1 and the subsequent regulatory fate of its substrates. The proposed research allows for significant insight into the cellular response to Pin1 protein modification as a consequence of lipid peroxidation.
Funding Period: 2012-05-01 - 2014-04-30
more information: NIH RePORT

Top Publications

  1. pmc Peptidyl-prolyl cis/trans-isomerase A1 (Pin1) is a target for modification by lipid electrophiles
    Christopher D Aluise
    Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232 0146, USA
    Chem Res Toxicol 26:270-9. 2013

Detail Information

Publications1

  1. pmc Peptidyl-prolyl cis/trans-isomerase A1 (Pin1) is a target for modification by lipid electrophiles
    Christopher D Aluise
    Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232 0146, USA
    Chem Res Toxicol 26:270-9. 2013
    ..The present study establishes that it is also a target for electrophilic modification by products of lipid peroxidation...

Research Grants30

  1. Mitochondrial Dysfunction in Neurodegeneration of Aging
    Gary E Gibson; Fiscal Year: 2013
    ..Successful completion of the goals of these projects can be expected to provide new insights into neurodegenerative processes and contribute to novel approaches to ameliorating age-related neurodegenerations. ..
  2. Targeting protein adduction by reactive aldehydes in Alzheimer's disease
    Olivier Boutaud; Fiscal Year: 2013
    ..It will also provide evidence for a new pharmacological target for development of drugs aimed at reducing levels of reactive aldehydes in AD. ..
  3. DEGENERATIVE AND DEMENTING DISEASES OF AGING
    Stanley B Prusiner; Fiscal Year: 2013
    ..The ultimate goal of all the proposed studies is to define the molecular events that feature in the formation of human prions in order to develop therapeutics that cure the human prion diseases. ..
  4. Mass Spectrometric Studies of Protein Oxidation: Aging and Environmental Factors
    Scott Gronert; Fiscal Year: 2013
    ..This information is critical for understanding the role of protein oxidation in mitochondrial dysfunction and for the development of biomarkers based on protein oxidation as well as the assessment of potential therapeutics. ..
  5. Isotropic Reinforcement to Minimize Nigrostriatal Degeneration
    AMY BEATRICE MANNING-BOG; Fiscal Year: 2013
    ..Importantly, if our hypotheses are correct, the window to an entirely new spectrum of therapeutic targets is opened for neurodegenerative and other disorders characterized by oxidative injury. ..
  6. A Gene therapeutic approach to stable suppression of HIV-1 replication
    MICHAEL R FARZAN; Fiscal Year: 2013
    ..These studies will establish principles and protocols directly applicable to subsequent human clinical trials. ..
  7. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  8. Lipid-Peroxidation Induced Cyclic Adducts in Hepatocarcinogenesis
    Fung Lung Chung; Fiscal Year: 2013
    ..The data generated from these studies will help us to understand the roles of endogenous cyclic Acr-dG and HNE-dG adducts from lipid peroxidation in hepatocarcinogenesis. ..
  9. Pathogenesis of the Metabolic Syndrome
    W Timothy Garvey; Fiscal Year: 2013
    ..These data will predictably identify new diagnostic biomarkers for insulin resistance and T2DM, and advance our understanding of molecular mechanisms underlying human insulin resistance. ..