Tyrosine 12 of human calcitonin modulates its amyloid formation, membrane binding, and bioactivity

I. Ching Hsieh, Ting Wei Chen, Ya Ping Chuang, Yun Ju Lai, Ling Hsien Tu*

*此作品的通信作者

研究成果: 雜誌貢獻期刊論文同行評審

摘要

Irreversible aggregation greatly limits the bioavailability and therapeutic activity of peptide-based drugs, so preventing protein or peptide aggregation is a common issue in drug formulation. Human calcitonin (hCT), a peptide hormone secreted by thyroidal parafollicular cells, can regulate blood calcium levels and maintain bone structure. Hence, it can be used as a treatment for metabolic bone diseases, such as osteoporosis and Paget's disease. However, hCT has a relatively high propensity to form amyloid fibrils that hinder its biological function and limit its pharmaceutical potential. In previous studies, we demonstrated, along with other research groups, that modifying specific residues of hCT is sufficient to prevent hCT aggregation. We proceeded to find the key residues that regulate the aggregation of hCT for a better understanding of the mechanism of hCT aggregation. In this work, we used amyloid propensity prediction software and found that Tyr12 may play a key role in regulating hCT aggregation. Thus, we propose three human calcitonin variants (Y12E, Y12P, Y12R) for hCT non-amyloidogenic substituents and examined the aggregation characteristics of variants using multiple biophysical techniques. Y12E showed the best anti-aggregation propensity and can work as inhibitor of hCT aggregation. We also found this residue is crucial for membrane binding and receptor binding. The data presented herein provides an overview of Tyr12 that should be carefully considered in peptide design.

原文英語
頁(從 - 到)121-129
頁數9
期刊Biochimie
197
DOIs
出版狀態已發佈 - 2022 6月

ASJC Scopus subject areas

  • 生物化學

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