Mispacking of the F87 sidechain drives aggregation‐promoting conformational fluctuations in the subunit interfaces of the transthyretin tetramer DOI
Xun Sun, James A. Ferguson, Ke Yang

et al.

Protein Science, Journal Year: 2024, Volume and Issue: 33(9)

Published: Aug. 16, 2024

Abstract Aberrant formation and deposition of human transthyretin (TTR) aggregates causes amyloidosis. To initialize aggregation, tetramers must first dissociate into monomers that partially unfold to promote entry the aggregation pathway. The native TTR tetramer (T) is stabilized by docking F87 sidechain an interfacial cavity enclosed several hydrophobic residues including A120. We have previously shown alternative (T*) with mispacked sidechains more prone dissociation than T state. However, molecular basis for reduced stability in T* remains unclear. Here we report characterization A120L mutant, where steric hindrance introduced binding site. x‐ray structure shows displaced from its site across subunit interface. In A120S, a naturally occurring pathogenic mutant less aggregation‐prone A120L, correctly docked, as tetramer. Nevertheless, 19 F‐NMR assays show elevated population monomeric intermediate A120S relative control containing A120, due accelerated slowed monomer tetramerization. mispacking associated enhanced exchange dynamics residues. At 298 K, populations various mutants fall between 4% 7% (Δ G ~ 1.5–1.9 kcal/mol), consistent free energy change expected undocking solvent exposure one four 1.6 kcal/mol). Our data provide molecular‐level picture likely universal tetrameric promotes conformational increases propensity.

Language: Английский

Mispacking of the F87 sidechain drives aggregation‐promoting conformational fluctuations in the subunit interfaces of the transthyretin tetramer DOI
Xun Sun, James A. Ferguson, Ke Yang

et al.

Protein Science, Journal Year: 2024, Volume and Issue: 33(9)

Published: Aug. 16, 2024

Abstract Aberrant formation and deposition of human transthyretin (TTR) aggregates causes amyloidosis. To initialize aggregation, tetramers must first dissociate into monomers that partially unfold to promote entry the aggregation pathway. The native TTR tetramer (T) is stabilized by docking F87 sidechain an interfacial cavity enclosed several hydrophobic residues including A120. We have previously shown alternative (T*) with mispacked sidechains more prone dissociation than T state. However, molecular basis for reduced stability in T* remains unclear. Here we report characterization A120L mutant, where steric hindrance introduced binding site. x‐ray structure shows displaced from its site across subunit interface. In A120S, a naturally occurring pathogenic mutant less aggregation‐prone A120L, correctly docked, as tetramer. Nevertheless, 19 F‐NMR assays show elevated population monomeric intermediate A120S relative control containing A120, due accelerated slowed monomer tetramerization. mispacking associated enhanced exchange dynamics residues. At 298 K, populations various mutants fall between 4% 7% (Δ G ~ 1.5–1.9 kcal/mol), consistent free energy change expected undocking solvent exposure one four 1.6 kcal/mol). Our data provide molecular‐level picture likely universal tetrameric promotes conformational increases propensity.

Language: Английский

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