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Cited by 61Protein Interaction Studies and Fluorescence AnalysisAntioxidant Activity and Oxidative StressRedox biology and oxidative stress

Characterization of 4-HNE Modified L-FABP Reveals Alterations in Structural and Functional Dynamics

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Smathers, Rebecca L., Fritz, Kristofer S., Galligan, James J., Shearn, Colin T., Reigan, Philip, Marks, Michael J., Petersen, Dennis R.·2012·PLoS ONE
DOI 10.1371/journal.pone.0038459PMC PMC3368874
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Abstract

4-Hydroxynonenal (4-HNE) is a reactive α,β-unsaturated aldehyde produced during oxidative stress and subsequent lipid peroxidation of polyunsaturated fatty acids. The reactivity of 4-HNE towards DNA and nucleophilic amino acids has been well established. In this report, using proteomic approaches, liver fatty acid-binding protein (L-FABP) is identified as a target for modification by 4-HNE. This lipid binding protein mediates the uptake and trafficking of hydrophobic ligands throughout cellular compartments. Ethanol caused a significant decrease in L-FABP protein (P<0.001) and mRNA (P<0.05), as well as increased poly-ubiquitinated L-FABP (P<0.001). Sites of 4-HNE adduction on mouse recombinant L-FABP were mapped using MALDI-TOF/TOF mass spectrometry on apo (Lys57 and Cys69) and holo (Lys6, Lys31, His43, Lys46, Lys57 and Cys69) L-FABP. The impact of 4-HNE adduction was found to occur in a concentration-dependent manner; affinity for the fluorescent ligand, anilinonaphthalene-8-sulfonic acid, was reduced from 0.347 µM to Kd(1) = 0.395 µM and Kd(2) = 34.20 µM. Saturation analyses revealed that capacity for ligand is reduced by approximately 50% when adducted by 4-HNE. Thermal stability curves of apo L-FABP was also found to be significantly affected by 4-HNE adduction (ΔTm = 5.44°C, P<0.01). Computational-based molecular modeling simulations of adducted protein revealed minor conformational changes in global protein structure of apo and holo L-FABP while more apparent differences were observed within the internal binding pocket, revealing reduced area and structural integrity. New solvent accessible portals on the periphery of the protein were observed following 4-HNE modification in both the apo and holo state, suggesting an adaptive response to carbonylation. The results from this study detail the dynamic process associated with L-FABP modification by 4-HNE and provide insight as to how alterations in structural integrity and ligand binding may a contributing factor in the pathogenesis of ALD.

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  • 4-HNE is more stable than other oxidative species, with a physiological half-life on the order of 2 min.

    “Complicating matters, 4-HNE is more stable than other oxidative species, with a physiological half-life on the order of 2 min [84].”

    From Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer’s Disease? (2022) · cites this paper as [84]

    The Introduction reports a 4-HNE half-life of approximately 2 minutes and says this allows it to migrate between intracellular sites. It does not compare 4-HNE’s stability with that of other oxidative species, so the comparative part of the claim is unsupported. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Authors
Smathers, R. L., Fritz, K. S., Galligan, J. J., Shearn, C. T., Reigan, P., Marks, M. J., & Petersen, D. R.
Affiliations
  • University of Colorado Anschutz (US)
  • University of Colorado Boulder (US)
Corresponding author
Petersen, Dennis R.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2012-06-06
Volume
7
Issue
6
Pages
e38459
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0038459
PMC
PMC3368874
OpenAlex
W2016992147
Cited by
61
References
0
Citations by year
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FWCI
2.65
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • National Institutes of Health
  • Cancer Center, University of Colorado
  • Anschutz Medical Campus, University of Colorado
  • National Institute on Alcohol Abuse and Alcoholism (F31AA018898, R37AA009300)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK074487)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
  • Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
alcoholic liver disease, 4-hydroxynonenal, lipid peroxidation, protein carbonylation, liver fatty acid binding protein, ethanol, ligand binding affinity, thermal stability, protein conformational change, ubiquitination, oxidative stress, molecular modeling, solvent accessibility
MeSH terms
Ethanol, Aldehydes, Anilino Naphthalenesulfonates, Animals, Cloning, Molecular, Gene Expression Regulation, Liver Diseases, Alcoholic, Male, Mice, Inbred C57BL, Models, Molecular, Protein Binding, Protein Conformation, Mass Spectrometry, Electrophoresis, Gel, Two-Dimensional, DNA Primers, Reverse Transcriptase Polymerase Chain Reaction, Proteomics, Immunoprecipitation, Fatty Acid-Binding Proteins, Mice, Ubiquitination

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