Interspecies Variation between Fish and Human Transthyretins in Their Binding of Thyroid-Disrupting ChemicalsClick to copy article linkArticle link copied!
- Jin Zhang
- Christin GrundströmChristin GrundströmDepartment of Chemistry, Umeå University, Umeå SE-90187, SwedenMore by Christin Grundström
- Kristoffer BrännströmKristoffer BrännströmDepartment of Medical Biochemistry and Biophysics, Umeå University, Umeå SE-90187, SwedenMore by Kristoffer Brännström
- Irina IakovlevaIrina IakovlevaDepartment of Chemistry, Umeå University, Umeå SE-90187, SwedenMore by Irina Iakovleva
- Mikael LindbergMikael LindbergDepartment of Chemistry, Umeå University, Umeå SE-90187, SwedenMore by Mikael Lindberg
- Anders OlofssonAnders OlofssonDepartment of Medical Biochemistry and Biophysics, Umeå University, Umeå SE-90187, SwedenMore by Anders Olofsson
- Patrik L. Andersson*Patrik L. Andersson*Phone: +46-(0)907865266; e-mail: [email protected]Department of Chemistry, Umeå University, Umeå SE-90187, SwedenMore by Patrik L. Andersson
- A. Elisabeth Sauer-Eriksson*A. Elisabeth Sauer-Eriksson*Phone: +46-(0)907865923; e-mail: [email protected]Department of Chemistry, Umeå University, Umeå SE-90187, SwedenMore by A. Elisabeth Sauer-Eriksson
Abstract
Thyroid-disrupting chemicals (TDCs) are xenobiotics that can interfere with the endocrine system and cause adverse effects in organisms and their offspring. TDCs affect both the thyroid gland and regulatory enzymes associated with thyroid hormone homeostasis. Transthyretin (TTR) is found in the serum and cerebrospinal fluid of vertebrates, where it transports thyroid hormones. Here, we explored the interspecies variation in TDC binding to human and fish TTR (exemplified by Gilthead seabream (Sparus aurata)). The in vitro binding experiments showed that TDCs bind with equal or weaker affinity to seabream TTR than to the human TTR, in particular, the polar TDCs (>500-fold lower affinity). Crystal structures of the seabream TTR–TDC complexes revealed that all TDCs bound at the thyroid binding sites. However, amino acid substitution of Ser117 in human TTR to Thr117 in seabream prevented polar TDCs from binding deep in the hormone binding cavity, which explains their low affinity to seabream TTR. Molecular dynamics and in silico alanine scanning simulation also suggested that the protein backbone of seabream TTR is more rigid than the human one and that Thr117 provides fewer electrostatic contributions than Ser117 to ligand binding. This provides an explanation for the weaker affinities of the ligands that rely on electrostatic interactions with Thr117. The lower affinities of TDCs to fish TTR, in particular the polar ones, could potentially lead to milder thyroid-related effects in fish.
Cited By
Smart citations by scite.ai include citation statements extracted from the full text of the citing article. The number of the statements may be higher than the number of citations provided by ACS Publications if one paper cites another multiple times or lower if scite has not yet processed some of the citing articles.
This article is cited by 5 publications.
- Aaron S. Birchfield, Faik N. Musayev, Abdul J. Castillo, George Zorn, Brian Fuglestad. Broad PFAS Binding with Fatty Acid Binding Protein 4 Is Enabled by Variable Binding Modes. JACS Au 2025, 5
(6)
, 2469-2474. https://doi.org/10.1021/jacsau.5c00504
- Zongzhe He, Yanhong Li, Liangliang Zhou, Rui Li, Yanqing Zhang, Zhen Wang, Minghua Wang. In Silico, In Vitro, and In Vivo Studies Indicate the Endocrine-Disrupting Effects of Cyproconazole Stereoisomers. Journal of Agricultural and Food Chemistry 2024, 72
(44)
, 24228-24236. https://doi.org/10.1021/acs.jafc.4c04927
- Alicia M. Crisalli, Ang Cai, Bongsup P. Cho. Probing the Interactions of Perfluorocarboxylic Acids of Various Chain Lengths with Human Serum Albumin: Calorimetric and Spectroscopic Investigations. Chemical Research in Toxicology 2023, 36
(4)
, 703-713. https://doi.org/10.1021/acs.chemrestox.3c00011
- Songshan Zhao, Xianhai Yang, Huihui Liu, Yue Xi, Jing Li. Potential Disrupting Effects of Wastewater-Derived Disinfection Byproducts on Chinese Rare Minnow (Gobiocypris rarus) Transthyretin: An In Vitro and In Silico Study. Environmental Science & Technology 2023, 57
(8)
, 3228-3237. https://doi.org/10.1021/acs.est.2c06192
- Jian Li, Ying Xu, Na Li, Rui Zuo, Yuanzheng Zhai, Haiyang Chen. Thyroid Hormone Disruption by Organophosphate Esters Is Mediated by Nuclear/Membrane Thyroid Hormone Receptors: In Vitro, In Vivo, and In Silico Studies. Environmental Science & Technology 2022, 56
(7)
, 4241-4250. https://doi.org/10.1021/acs.est.1c05956
Article Views
Altmetric
Citations
Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.
Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.
The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.