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To initialize aggregation, transthyretin tetramers must first dissociate into monomers that partially unfold to promote entry into the aggregation pathway. The native TTR tetramer (T) is stabilized by docking of the F87 sidechain into an interfacial cavity enclosed by several hydrophobic residues including A120. We have previously shown that an alternative tetramer (T*) with mispacked F87 sidechains is more prone to dissociation and aggregation than the native T state. However, the molecular basis for the reduced stability in T* remains unclear. Here we report characterization of the A120L mutant, where steric hindrance is introduced into the F87 binding site. The x\u2010ray structure of A120L shows that the F87 sidechain is displaced from its docking site across the subunit interface. In A120S, a naturally occurring pathogenic mutant that is less aggregation\u2010prone than A120L, the F87 sidechain is correctly docked, as in the native TTR tetramer. Nevertheless,\n                    <jats:sup>19<\/jats:sup>\n                    F\u2010NMR aggregation assays show an elevated population of a monomeric aggregation intermediate in A120S relative to a control containing the native A120, due to accelerated tetramer dissociation and slowed monomer tetramerization. The mispacking of the F87 sidechain is associated with enhanced exchange dynamics for interfacial residues. At 298\u2009K, the T* populations of various naturally occurring mutants fall between 4% and 7% (\u0394\n                    <jats:italic>G<\/jats:italic>\n                    \u2009~\u20091.5\u20131.9\u2009kcal\/mol), consistent with the free energy change expected for undocking and solvent exposure of one of the four F87 sidechains in the tetramer (\u0394\n                    <jats:italic>G<\/jats:italic>\n                    \u2009~\u20091.6\u2009kcal\/mol). Our data provide a molecular\u2010level picture of the likely universal F87 sidechain mispacking in tetrameric TTR that promotes interfacial conformational dynamics and increases aggregation propensity.\n                  <\/jats:p>","DOI":"10.1002\/pro.5101","type":"journal-article","created":{"date-parts":[[2024,8,16]],"date-time":"2024-08-16T07:14:21Z","timestamp":1723792461000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Mispacking of the\n                    <scp>F87<\/scp>\n                    sidechain drives aggregation\u2010promoting conformational fluctuations in the subunit interfaces of the transthyretin tetramer"],"prefix":"10.1002","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8079-5530","authenticated-orcid":false,"given":"Xun","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Integrative Structural and Computational Biology and Skaggs Institute of Chemical Biology, The Scripps Research Institute  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2891-0850","authenticated-orcid":false,"given":"James A.","family":"Ferguson","sequence":"additional","affiliation":[{"name":"Department of Integrative Structural and Computational Biology and Skaggs Institute of Chemical Biology, The Scripps Research Institute  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Integrative Structural and Computational Biology and Skaggs Institute of Chemical Biology, The Scripps Research Institute  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robyn L.","family":"Stanfield","sequence":"additional","affiliation":[{"name":"Department of Integrative Structural and Computational Biology and Skaggs Institute of Chemical Biology, The Scripps Research Institute  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6855-3398","authenticated-orcid":false,"given":"H. Jane","family":"Dyson","sequence":"additional","affiliation":[{"name":"Department of Integrative Structural and Computational Biology and Skaggs Institute of Chemical Biology, The Scripps Research Institute  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1368-0223","authenticated-orcid":false,"given":"Peter E.","family":"Wright","sequence":"additional","affiliation":[{"name":"Department of Integrative Structural and Computational Biology and Skaggs Institute of Chemical Biology, The Scripps Research Institute  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,8,16]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.20821"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2836(78)90368-6"},{"key":"e_1_2_10_4_1","volume-title":"AMBER 2016","author":"Case 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