Investigation of the impact of nonsynonymous mutations on thyroid peroxidase dimer

• Published in: PloS one Vol. 18; no. 9; p. e0291386
• Main Authors: Begum, Mst. Noorjahan, Mahtarin, Rumana, Ahmed, Sinthyia, Shahriar, Imrul, Hossain, Shekh Rezwan, Mia, Md. Waseque, Qadri, Syed Saleheen, Qadri, Firdausi, Mannoor, Kaiissar, Akhteruzzaman, Sharif
• Format: Journal Article
• Language: English
• Published: San Francisco Public Library of Science 12.09.2023; Public Library of Science (PLoS)
• Subjects: Analysis; Biology and Life Sciences; Biosynthesis; Congenital diseases; Defects; Development and progression; Dimers; Endocrine disorders; Enzymatic activity; Gene mutations; Genetic aspects; Genetic disorders; Health aspects; Hormones; Hydrogen peroxide; Hypothyroidism; Investigations; Iodide peroxidase; Iodination; Ligands; Medical research; Medicine, Experimental; Molecular docking; Molecular dynamics; Molecular structure; Monomers; Mutation; Optimization; Peroxidase; Physical Sciences; Physiological aspects; Principal components analysis; Proteins; Research and Analysis Methods; Simulation; Symmetry; Thyroid; Thyroid gland; Thyroid hormones; Bangladesh
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0291386

Congenital hypothyroidism is one of the most common preventable endocrine disorders associated with thyroid dysgenesis or dyshormonogenesis. Thyroid peroxidase (TPO) gene defect is mainly responsible for dyshormonogenesis; a defect in the thyroid hormone biosynthesis pathway. In Bangladesh, there is limited data regarding the genetic etiology of Congenital Hypothyroidism (CH). The present study investigates the impact of the detected mutations (p.Ala373Ser, and p.Thr725Pro) on the TPO dimer protein. We have performed sequential molecular docking of H.sub.2 O.sub.2 and I.sup.- ligands with both monomers of TPO dimer to understand the iodination process in thyroid hormone biosynthesis. Understanding homodimer interactions at the atomic level is a critical challenge to elucidate their biological mechanisms of action. The docking results reveal that mutations in the dimer severely disrupt its catalytic interaction with essential ligands. Molecular dynamics simulation has been performed to validate the docking results, thus realizing the consequence of the mutation in the biological system's mimic. The dynamics results expose that mutations destabilize the TPO dimer protein. Finally, principal component analysis exhibits structural and energy profile discrepancies in wild-type and mutant dimers. The findings of this study highlight that the mutations in TPO protein can critically affect the dimer structure and loss of enzymatic activity is persistent. Other factors also might influence the hormone synthesis pathway, which is under investigation.