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Tafamidis can restore the stability of some mutant TTR tetramers and slow down the progression of <jats:italic>TTR<\/jats:italic>\u2010FAP. However, there is little understanding of the biophysical features of A97S\u2010TTR mutant and the pharmacological modulation effect of tafamidis on it. This study aims to delineate the biophysical characteristics of A97S\u2010TTR and the pharmacological modulation effect of tafamidis on this mutant.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>The stability of TTR tetramers was assessed by urea denaturation and differential scanning calorimetry. Isothermal titration calorimetry (ITC) was used to measure the binding constant of tafamidis to TTR. Nuclear magnetic resonance spectroscopy (NMR) titration experiment was used to map out the tafamidis binding site.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Chemical and thermal denaturation confirmed the destabilization effect of A97S. Consistent with other the amyloidogenic mutant, A97S\u2010TTR has slightly lower conformational stability. NMR revealed the binding site of A97S\u2010TTR with tafamidis is at the thyroxine binding pocket. The ITC experiments documented the high affinity of the binding which can effectively stabilize the A97S\u2010TTR tetramer.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>This study confirmed the structural modulation effect of tafamidis on A97S\u2010TTR and implied the potential therapeutic benefit of tafamidis for A97S <jats:italic>TTR<\/jats:italic>\u2010FAP. This approach can be applied to investigate the modulation effect of tafamidis on other rare <jats:italic>TTR<\/jats:italic> variants and help to make individualized choices of available treatments for FAP patients.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.50887","type":"journal-article","created":{"date-parts":[[2019,9,10]],"date-time":"2019-09-10T08:40:18Z","timestamp":1568104818000},"page":"1961-1970","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Biophysical characterization and modulation of Transthyretin Ala97Ser"],"prefix":"10.1002","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5902-3870","authenticated-orcid":false,"given":"Yo\u2010Tsen","family":"Liu","sequence":"first","affiliation":[{"name":"Division of Epilepsy Neurological Institute Taipei Veterans General Hospital Taipei Taiwan"},{"name":"National Yang\u2010Ming University School of Medicine Taipei Taiwan"},{"name":"Institute of 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