Structural polymorphism of ex-vivo ALECT2 amyloid fibrils revealed by cryo-EM
ALECT2 amyloidosis is a rare systemic disease characterized by the pathological deposition of leukocyte cell-derived chemotaxin-2 (LECT2) as amyloid fibrils, primarily affecting the kidneys and liver. The molecular mechanisms underlying LECT2 aggregation remain poorly defined, hindering diagnostic and therapeutic development. Here, we present cryo-electron microscopy structures of ex-vivo ALECT2 fibrils extracted from a patient's kidney. We identified three fibril polymorphs: a predominant single-protofilament morphology and two minor double-protofilament morphologies. The dominant single-protofilament morphology comprises the full-length 133-residue LECT2 protein and retains all three native disulfide bonds. Low-resolution reconstructions of double-protofilament morphologies suggest they adopt a similar fold to the single protofilament morphology, but form paired assemblies with different inter-filament interfaces. Mass spectrometry also reveals acetylation within the fibrils. These findings offer critical insights into the structural basis of ALECT2 amyloid formation and identify molecular features that could inform future diagnostic and therapeutic approaches.
Authors
- Lorena Saelices (ORCID: https://orcid.org/0000-0002-1904-2150)
- Shumaila Afrin (ORCID: https://orcid.org/0000-0002-8671-1617)
- Yasmin Ahmed (ORCID: https://orcid.org/0000-0002-5115-2085)
- Andrew S. Lemoff (ORCID: https://orcid.org/0000-0002-4943-0170)
- Parker Bassett (ORCID: https://orcid.org/0009-0001-5162-7212)
- Raja Reddy Kallem (ORCID: https://orcid.org/0000-0003-1859-7063)
- Christian López (ORCID: https://orcid.org/0009-0005-1820-0144)
- 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)
- Li Li (ORCID: https://orcid.org/0000-0003-2064-2177)
- Maja Pękala (ORCID: https://orcid.org/0009-0000-8362-7607)
- Barbara Kluve-Beckerman
- Preeti Singh
- Christos Argyropoulos
Institutions
- Texas Tech University (US)
- University of New Mexico (US)
- Southwestern Medical Center (US)
- Indiana University School of Medicine
- Indiana University – Purdue University Indianapolis (US)
- The University of Texas Southwestern Medical Center (US)
- Texas Tech University Health Sciences Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-04-11
- DOI
- https://doi.org/10.1038/s41467-026-71223-3
- Primary Topic
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Welch Foundation
- American Heart Association
- National Heart, Lung, and Blood Institute