Abstract
Transthyretin (TTR) amyloidosis is a protein misfolding disease characterized by amyloid fibril deposition in vital organs, leading to cardiomyopathy (ATTR-CM). Early diagnosis of ATTR-CM remains challenging due to lack of sensitive, rapid screening methods. Here, we report cryo-EM structures of TTR amyloid fibrils extracted from minimally invasive abdominal fat-pad biopsies of three living Ala97Ser ATTR-CM patients. The adipose-derived fibril structures closely mirror those from diseased post-mortem cardiac tissues, validating the use of fat-pad biopsies to investigate the atomic structure of TTR fibrils in living patients. Furthermore, we determined cryo-EM structures of TTR fibrils in complex with two amyloid-binding dyes, Congo Red (CR) and Thioflavin S (ThS), which are widely used in the clinical diagnosis of ATTR-CM. Both CR and ThS predominantly bind to a specific surface arginine site on the TTR fibril via electrostatic interactions. These findings provide structural insights into how small-molecule dyes bind TTR fibrils, offering a molecular foundation for the rational design of TTR-specific tracers to enable early and accurate diagnosis of TTR amyloidosis.
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Acknowledgements
We thank the Cryo-EM Center at the Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry for help with cryo-EM data collection. We thank Dingfei Yan and Dr. Haiteng Deng in Center of Protein Analysis Technology, Tsinghua University, for MS analysis. This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No. XDB1060000 to C.L.), the National Natural Science Foundation (NSF) of China (32494764 and 92353302 to D.L.; 22425704 and 82188101 to C.L.; 32501045 to B.M.), Shanghai Basic Research Pioneer Project to C.L., the Shanghai Pilot Program for Basic Research - Chinese Academy of Science, Shanghai Branch (Grant No. JCYJ-SHFY-2022-005 to C.L.), the Postdoctoral Fellowship Program of CPSF (Grant No. GZB20230801 to B.M.), the China Postdoctoral Science Foundation (Grant No. 2024M753382 to B.M.), and the Shanghai Postdoctoral Excellence Program (Grant No. 2023725 to B.M.). Dr. Cong Liu is a SANS Exploration Scholar.
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Ma, B., Yao, Y., Wang, Q. et al. Structures of dye-bound transthyretin amyloid fibrils from abdominal fat biopsies. Nat Commun (2026). https://doi.org/10.1038/s41467-026-72441-5
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DOI: https://doi.org/10.1038/s41467-026-72441-5
