A new study in PNAS, achieved by Prof. LIU Cong at the Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, CAS, reported the high-resolution structures of amyloid fibrils directly extracted from biopsy samples of living patients with systemic light chain (AL) amyloidosis, providing new molecular insights into how patient-specific protein sequences and tissue environments shape amyloid architecture. In this study, the team analyzed amyloid fibrils isolated from abdominal fat and cardiac biopsies obtained from three AL amyloidosis patients. Using cryo-electron microscopy (cryo-EM), they resolved five distinct atomic structures of immunoglobulin light chain–derived fibrils. Unlike most previous structural studies, which relied on postmortem or explanted tissues, this work focuses on fibrils derived from clinically accessible biopsies of living patients, offering a closer view of disease-relevant amyloid structures. A key finding of the study is the pronounced patient-specific structural diversity of amyloid fibrils. Fibrils from different patients adopt distinct atomic conformations, even when derived from the same immunoglobulin light chain germline family. This highlights the dominant role of individual protein sequences and patient-specific variations in defining fibril architecture. In contrast, amyloid fibrils extracted from different tissues within the same patient—most notably abdominal fat and heart—exhibit highly conserved global folds. Although subtle local differences were observed, including side-chain rearrangements and additional densities near the fibril surface, the overall fibril architecture remains remarkably similar across tissues. These localized variations are likely influenced by tissue-specific microenvironments and associated molecular cofactors. The discovery has important clinical implications. Abdominal fat biopsy is widely used as a minimally invasive diagnostic tool for AL amyloidosis, yet it has remained unclear whether fibrils obtained from fat accurately represent those deposited in vital organs such as the heart. The structural similarity revealed in this study provides direct molecular evidence supporting the diagnostic relevance of fat-derived amyloid fibrils. Beyond structural comparisons, the researchers identified conserved aggregation-prone regions, disulfide bonds, and posttranslational modifications within light chain fibrils. Additional non-proteinaceous or protein-associated densities were frequently observed adjacent to aromatic residues, suggesting that extracellular matrix components or other tissue-derived cofactors may participate in fibril stabilization and polymorphism. By integrating cryo-EM, mass spectrometry, and biochemical analyses, this work establishes a biopsy-resolved structural framework for understanding AL amyloidosis. The findings underscore how intrinsic protein sequences and extrinsic tissue environments jointly determine amyloid structure, paving the way for improved diagnostic strategies and the rational development of amyloid-targeting therapeutics.
LIU Cong Ph.D. Professor Interdisciplinary Research Center on Biology and Chemistry (IRCBC) Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences Haike Road 345 Shanghai 201204 China Email: liulab@sioc.ac.cn |
