6FXU

Crystal structure of human transthyretin mutant T119M at pH 5.5

6FXU の概要

• エントリーDOI: 10.2210/pdb6fxu/pdb
• 分子名称: Transthyretin (2 entities in total)
• 機能のキーワード: amyloid, gatekeeper, aggregation, stability, transport protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 27614.90

構造登録者

Varejao, N.,Esperante, S.,Ventura, S.,Reverter, D. (登録日: 2018-03-09, 公開日: 2019-03-20, 最終更新日: 2024-02-07)

主引用文献

Esperante, S.A.,Varejao, N.,Pinheiro, F.,Sant'Anna, R.,Luque-Ortega, J.R.,Alfonso, C.,Sora, V.,Papaleo, E.,Rivas, G.,Reverter, D.,Ventura, S.
Disease-associated mutations impacting BC-loop flexibility trigger long-range transthyretin tetramer destabilization and aggregation.
J.Biol.Chem., 297:101039-101039, 2021

PubMed Abstract: Hereditary transthyretin amyloidosis (ATTR) is an autosomal dominant disease characterized by the extracellular deposition of the transport protein transthyretin (TTR) as amyloid fibrils. Despite the progress achieved in recent years, understanding why different TTR residue substitutions lead to different clinical manifestations remains elusive. Here, we studied the molecular basis of disease-causing missense mutations affecting residues R34 and K35. R34G and K35T variants cause vitreous amyloidosis, whereas R34T and K35N mutations result in amyloid polyneuropathy and restrictive cardiomyopathy. All variants are more sensitive to pH-induced dissociation and amyloid formation than the wild-type (WT)-TTR counterpart, specifically in the variants deposited in the eyes amyloid formation occurs close to physiological pHs. Chemical denaturation experiments indicate that all the mutants are less stable than WT-TTR, with the vitreous amyloidosis variants, R34G and K35T, being highly destabilized. Sequence-induced stabilization of the dimer-dimer interface with T119M rendered tetramers containing R34G or K35T mutations resistant to pH-induced aggregation. Because R34 and K35 are among the residues more distant to the TTR interface, their impact in this region is therefore theorized to occur at long range. The crystal structures of double mutants, R34G/T119M and K35T/T119M, together with molecular dynamics simulations indicate that their strong destabilizing effect is initiated locally at the BC loop, increasing its flexibility in a mutation-dependent manner. Overall, the present findings help us to understand the sequence-dynamic-structural mechanistic details of TTR amyloid aggregation triggered by R34 and K35 variants and to link the degree of mutation-induced conformational flexibility to protein aggregation propensity.

PubMed: 34343569
DOI: 10.1016/j.jbc.2021.101039

実験手法

X-RAY DIFFRACTION (1.359 Å)