9D23

Cryo-EM structure of amyloid fibril extracted from heart of a variant ATTR T60A amyloidosis patient 2

9D23 の概要

• エントリーDOI: 10.2210/pdb9d23/pdb
• 関連するPDBエントリー: 9D21
• EMDBエントリー: 46479 46481
• 分子名称: Transthyretin (1 entity in total)
• 機能のキーワード: transthyretin, amyloidosis, attr, cardiac, protein fibril
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 68736.67

構造登録者

Nguyen, A.B.,Fernandez-Ramirez, M.C.,Saelices, L. (登録日: 2024-08-08, 公開日: 2025-08-13, 最終更新日: 2025-12-17)

主引用文献

Fernandez-Ramirez, M.D.C.,Nguyen, B.A.,Afrin, S.,Singh, V.,Evers, B.,Shelton, J.M.,Escobar, C.L.,Bassett, P.,Wang, L.,Pekala, M.,Ahmed, Y.,Cabrera Hernandez, L.O.,Pedretti, R.,Singh, P.,Canepa, J.,Wosztyl, A.,Li, Y.,Boyer, D.R.,Cao, Q.,Saelices, L.
Structural and molecular homogeneity of ATTRv-T60A amyloid fibrils across patients and organs.
Structure, 33:2013-2019.e4, 2025

PubMed Abstract: Transthyretin amyloidosis is a systemic protein misfolding disorder with diverse clinical phenotypes, including cardiomyopathy, polyneuropathy, or a combination of both. While structural polymorphism of amyloid fibrils has been linked to disease heterogeneity in neurodegenerative disorders, its role in transthyretin amyloidosis remains unclear. Here, we used cryo-electron microscopy to analyze ex vivo fibrils extracted from the hearts of three patients carrying the T60A mutation, a variant associated with mixed cardiac and neuropathic symptoms. In one patient, we additionally examined fibrils from the thyroid, kidney, and liver. All fibrils across patients and tissues adopted a single morphology previously associated with cardiomyopathy. Complementary molecular analyses revealed high compositional homogeneity. Notably, we extracted fibrils from the liver, an organ considered fibril-free, with seeding capacity in vitro. These findings suggest structural homogeneity as a hallmark of cardiac and mixed phenotypes, and provide a mechanistic rationale for the transmission of amyloidosis following domino liver transplantation.

PubMed: 41106377
DOI: 10.1016/j.str.2025.09.008

実験手法

ELECTRON MICROSCOPY (3.18 Å)