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Archives of Toxicology

, Volume 90, Issue 1, pp 217–227 | Cite as

Interaction of perfluoroalkyl acids with human liver fatty acid-binding protein

  • Nan Sheng
  • Juan Li
  • Hui Liu
  • Aiqian Zhang
  • Jiayin Dai
Organ Toxicity and Mechanisms

Abstract

Perfluoroalkyl acids (PFAAs) are highly persistent and bioaccumulative, resulting in their broad distribution in humans and the environment. The liver is an important target for PFAAs, but the mechanisms behind PFAAs interaction with hepatocyte proteins remain poorly understood. We characterized the binding of PFAAs to human liver fatty acid-binding protein (hL-FABP) and identified critical structural features in their interaction. The binding interaction of PFAAs with hL-FABP was determined by fluorescence displacement and isothermal titration calorimetry (ITC) assay. Molecular simulation was conducted to define interactions at the binding sites. ITC measurement revealed that PFOA/PFNA displayed a moderate affinity for hL-FABP at a 1:1 molar ratio, a weak binding affinity for PFHxS and no binding for PFHxA. Moreover, the interaction was mainly mediated by electrostatic attraction and hydrogen bonding. Substitution of Asn111 with Asp caused loss of binding affinity to PFAA, indicating its crucial role for the initial PFAA binding to the outer binding site. Substitution of Arg122 with Gly caused only one molecule of PFAA to bind to hL-FABP. Molecular simulation showed that substitution of Arg122 increased the volume of the outer binding pocket, making it impossible to form intensive hydrophobic stacking and hydrogen bonds with PFOA, and highlighting its crucial role in the binding process. The binding affinity of PFAAs increased significantly with their carbon number. Arg122 and Asn111 played a pivotal role in these interactions. Our findings may help understand the distribution pattern, bioaccumulation, elimination, and toxicity of PFAAs in humans.

Keywords

Perfluorinated compounds Human liver fatty acid-binding protein Interaction Isothermal titration calorimetry Molecular simulation 

Notes

Acknowledgments

This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB14000000) and the National Natural Science Foundation of China (grants 31320103915 and 31025006 for Dai, 21277164 for Zhang).

Conflict of interest

The authors declare they have no competing financial interests.

Supplementary material

204_2014_1391_MOESM1_ESM.docx (2.3 mb)
Supplementary material 1 (DOCX 2340 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Key Laboratory of Animal Ecology and Conservation Biology, Institute of ZoologyChinese Academy of SciencesBeijingPeople’s Republic of China
  2. 2.State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental SciencesChinese Academy of SciencesBeijingPeople’s Republic of China

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