Polymorphic IGLV6-57 AL amyloid fibrils and features of a shared folding pathway
Immunoglobulin light chain (AL) amyloidosis is a systemic disorder caused by the misfolding and aggregation of free immunoglobulin light chains (LCs) secreted by abnormal plasma cells. The resulting amyloid fibrils deposit in multiple organs, leading to progressive dysfunction and increased morbidity and mortality. Despite recent advances, the molecular determinants of LC aggregation and their effect on phenotypic variability are not fully defined. Structural characterization of ex-vivo fibrils provides insights into the underlying amyloidogenic processes that may affect the downstream pathogenesis. Here, we report cryo-electron microscopy structures of cardiac AL amyloid fibrils derived from an IGLV6-57 light chain. The fibrils display two distinct morphologies composed of single and double protofilaments, each adopting a previously unobserved fold. Comparison with previously reported AL fibril structures reveals that while individual mutations can alter the local conformation, IGLV6-57-derived fibrils share conserved structural motifs that may underlie common aggregation pathways. These findings expand the disease structural landscape and highlight sequence-dependent yet structurally constrained mechanisms of LC fibril formation. Researchers use cryogenic electron microscopy to study the unique structure of amyloid fibrils from the heart of a patient with AL amyloidosis. The amyloid fibrils display polymorphic structures, and share some similarities to previously determined structures.
Authors
- Lorena Saelices (ORCID: https://orcid.org/0000-0002-1904-2150)
- Shumaila Afrin (ORCID: https://orcid.org/0000-0002-8671-1617)
- Stephen S. Chung (ORCID: https://orcid.org/0000-0002-1433-7419)
- Yasmin Ahmed (ORCID: https://orcid.org/0000-0002-5115-2085)
- John R. Yates (ORCID: https://orcid.org/0000-0001-5267-1672)
- Gareth J. Morgan (ORCID: https://orcid.org/0000-0002-1275-2010)
- Parker Bassett (ORCID: https://orcid.org/0009-0001-5162-7212)
- Lori R. Roth (ORCID: https://orcid.org/0000-0003-0399-8315)
- Gurbakhash Kaur (ORCID: https://orcid.org/0000-0002-2510-6536)
- James J. Moresco (ORCID: https://orcid.org/0000-0003-1178-1642)
- Virender Singh (ORCID: https://orcid.org/0000-0002-6720-8784)
- Bret M. Evers (ORCID: https://orcid.org/0000-0001-5686-0315)
- Binh A. Nguyen (ORCID: https://orcid.org/0000-0001-7055-8809)
- Rose Pedretti (ORCID: https://orcid.org/0000-0001-6354-3588)
- Patrick T. Garrett (ORCID: https://orcid.org/0000-0002-8434-9693)
- Christian Lopez Escobar (ORCID: https://orcid.org/0009-0005-1820-0144)
- Maja Pękała
- Joshua Eddy
- Justin L. Grodin
Institutions
- Scripps Research Institute (US)
- Boston Medical Center (US)
- Southwestern Medical Center (US)
- Amyloidosis Foundation (US)
- The University of Texas Southwestern Medical Center (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-07-23
- DOI
- https://doi.org/10.1038/s41467-026-75958-x
- Primary Topic
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Pfizer
- AstraZeneca
- Cancer Prevention and Research Institute of Texas
- University of Texas Southwestern Medical Center
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- National Institute of General Medical Sciences
- SLAC National Accelerator Laboratory