Structural polymorphism of ex-vivo ALECT2 amyloid fibrils revealed by cryo-EM
Year: 2026
Type: article
Abstract: 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.
Source: Nature Communications
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: Welch Foundation, American Heart Association, Cancer Prevention and Research Institute of Texas, University of Texas Southwestern Medical Center, National Institutes of Health, University of California, Los Angeles, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, SLAC National Accelerator Laboratory
Awards: Closing the gap between structural biology and translational science for amyloid diseases, Establish New Cryo-EM Core Services to Drive Cancer Research and Drug Discovery at UTSouthwestern Medical Center, Study of the phenotypic variability of cardiac amyloidosis to develop peptide-based diagnostic tools, G3534087081, G3877668150, G5001072352, G563813673, G5806950731, The Stanford-SLAC CryoEM Center, G8255659214, ChimeraX -- Next Generation Visualization and Analysis Software for Multiscale Modeling
OpenAlex ID: W7153478044