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Aggregation of transthyretin (TTR) causes the TTR amyloidoses. The native TTR tetramer (a dimer of dimers) is stabilized by packing of phenylalanine 87 (F87) into a hydrophobic cavity of a neighboring protomer across the strong dimer-dimer interface. X-ray structures at acidic pH show that the side chain of F87 can be displaced from its binding pocket, but the resultant solution conformations remain unknown. Here we used 19F-NMR and 19F-labeled C10S-S85C TTR to characterize two local conformations of the loop containing F87. At neutral pH, F87 packs correctly into the inter-protomer cavity in the dominant conformational state (population 93%, T) whereas the remaining minor population is a mispacked tetramer (T*). The population of T* can be enhanced in heterotetramers by mixing C10S-S85C TTR with increasing molar ratios of A120L TTR, where a bulky leucine residue is introduced to disfavor the T state by steric hindrance.Exchange between the T and T* states in the presence of A120L is mediated by subunit exchange from the C10S-S85C tetramer. Compared to the TTR tetramer in which the dimers are correctly packed, mispacking of one or both dimer pairs leads to an increase of the urea-unfolding rate by 4-fold and at least 15-fold, respectively. Consistent acid-mediated tetramer dissociation was observed by 19F-NMR aggregation assays. Our results highlight the important role of the inter-protomer F87 side chain packing in determining the kinetic stability of the TTR tetramer; mispacking of F87 in the T* state predisposes it for rapid dissociation and entry into the aggregation pathway.

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