9FAC

Additional cryo-EM structure of cardiac amyloid AL59 - mixed polymorph

9FAC の概要

• エントリーDOI: 10.2210/pdb9fac/pdb
• 関連するPDBエントリー: 9FAA
• EMDBエントリー: 50272
• 分子名称: Monoclonal immunoglobulin light chains (LC), 2-acetamido-2-deoxy-beta-D-glucopyranose (2 entities in total)
• 機能のキーワード: systemic al amyloid fibril, protein fibril
• 由来する生物種: Homo sapiens
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 70722.71

構造登録者

Schulte, T.,Speranzini, V.,Chaves-Sanjuan, A.,Milazzo, M.,Ricagno, S. (登録日: 2024-05-10, 公開日: 2024-08-14, 最終更新日: 2025-07-02)

主引用文献

Schulte, T.,Chaves-Sanjuan, A.,Speranzini, V.,Sicking, K.,Milazzo, M.,Mazzini, G.,Rognoni, P.,Caminito, S.,Milani, P.,Marabelli, C.,Corbelli, A.,Diomede, L.,Fiordaliso, F.,Anastasia, L.,Pappone, C.,Merlini, G.,Bolognesi, M.,Nuvolone, M.,Fernandez-Busnadiego, R.,Palladini, G.,Ricagno, S.
Helical superstructures between amyloid and collagen in cardiac fibrils from a patient with AL amyloidosis.
Nat Commun, 15:6359-6359, 2024

PubMed Abstract: Systemic light chain (LC) amyloidosis (AL) is a disease where organs are damaged by an overload of a misfolded patient-specific antibody-derived LC, secreted by an abnormal B cell clone. The high LC concentration in the blood leads to amyloid deposition at organ sites. Indeed, cryogenic electron microscopy (cryo-EM) has revealed unique amyloid folds for heart-derived fibrils taken from different patients. Here, we present the cryo-EM structure of heart-derived AL amyloid (AL59) from another patient with severe cardiac involvement. The double-layered structure displays a u-shaped core that is closed by a β-arc lid and extended by a straight tail. Noteworthy, the fibril harbours an extended constant domain fragment, thus ruling out the variable domain as sole amyloid building block. Surprisingly, the fibrils were abundantly concatenated with a proteinaceous polymer, here identified as collagen VI (COLVI) by immuno-electron microscopy (IEM) and mass-spectrometry. Cryogenic electron tomography (cryo-ET) showed how COLVI wraps around the amyloid forming a helical superstructure, likely stabilizing and protecting the fibrils from clearance. Thus, here we report structural evidence of interactions between amyloid and collagen, potentially signifying a distinct pathophysiological mechanism of amyloid deposits.

PubMed: 39069558
DOI: 10.1038/s41467-024-50686-2

実験手法

ELECTRON MICROSCOPY (3.9 Å)