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Ala97Ser (A97S) is the major mutation reported in Taiwanese ATTR patients. Here, we combine atomic resolution structural information together with the biochemical data to demonstrate that substitution of polar Ser for a small hydrophobic side chain of Ala at residue 97 of TTR largely influences the local packing density of the FG\u2010loop, thus leading to the conformational instability of native tetramer, the increased monomeric species, and thus the enhanced amyloidogenicity of apo\u2010A97S. Based on calorimetric studies, the tetramer destabilization of A97S can be substantially altered by interacting with native stabilizers via similarly energetic patterns compared to that of wild\u2010type (WT) TTR; however, stabilizer binding partially rearranges the networks of hydrogen bonding in TTR variants while FG\u2010loops of tetrameric A97S still remain relatively flexible<jats:italic>.<\/jats:italic> Moreover, TTR in complexed with holo\u2010retinol binding protein 4 is slightly influenced by the structural and dynamic changes of FG\u2010loop caused by A97S substitution with an approximately five\u2010fold difference in binding affinity. Collectively, our findings suggest that the amyloidogenic A97S mutation destabilizes TTR by increasing the flexibility of the FG\u2010loop in the monomer, thus modulating the rate of amyloid fibrillization.<\/jats:p>","DOI":"10.1002\/pro.4610","type":"journal-article","created":{"date-parts":[[2023,3,5]],"date-time":"2023-03-05T06:23:25Z","timestamp":1677997405000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A molecular basis for tetramer destabilization and aggregation of transthyretin <scp>Ala97Ser<\/scp>"],"prefix":"10.1002","volume":"32","author":[{"given":"Yi\u2010Shiang","family":"Wang","sequence":"first","affiliation":[{"name":"Institute of Biochemistry and Molecular Biology College of Medicine, National Taiwan University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun\u2010Hsiang","family":"Huang","sequence":"additional","affiliation":[{"name":"Protein diffraction 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