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TitleCryo-EM structures of ALECT2 filaments from human renal biopsies.
Journal, issue, pagesNat Commun, Year 2026
Publish dateMay 22, 2026
AuthorsJian-Lin Zheng / Yu-Xin Zheng / Kai Chen / Shuang Wang / Jia-Wei Liang / Su-Xia Wang / Li Yang / Yang Shi /
PubMed AbstractLeukocyte chemotactic factor 2 is a recently identified amyloidogenic protein, whose abnormal aggregation defines a systemic amyloidosis termed ALECT2 amyloidosis. Due to the lack of reliable ...Leukocyte chemotactic factor 2 is a recently identified amyloidogenic protein, whose abnormal aggregation defines a systemic amyloidosis termed ALECT2 amyloidosis. Due to the lack of reliable biomarkers, diagnosis relies primarily on histological demonstration and typing of amyloid deposits in renal biopsies. However, immunohistochemical detection of ALECT2 is often inconsistent, leading to diagnostic uncertainty. The underlying basis remains poorly understood, reflecting our limited knowledge of ALECT2 deposits. Here, using cryo-electron microscopy (cryo-EM), we determined the structures of ALECT2 filaments from renal biopsies of five living patients. Unlike filaments assembled from recombinant proteins in vitro, all 133 residues of mature LECT2 are incorporated into the filament cores, with native disulfide linkages preserved. The filaments consistently adopt the shared six-layered folds in all five patients, indicating a common mechanism of amyloidogenesis. Because all residues are incorporated into the fibril core, epitope accessibility is limited. This can explain variability in immunohistochemical detection and thus highlights the need for conformation-specific antibodies and antibody-independent detection strategies for improving diagnostic accuracy. This biopsy-based workflow not only expands the availability of patient-derived tissue for cryo-EM studies but also demonstrates the potential of cryo-EM as a tool for precise diagnosis of systemic amyloidosis.
External linksNat Commun / PubMed:42173881
MethodsEM (helical sym.)
Resolution1.95 - 3.09 Å
Structure data

EMDB-66046, PDB-9wl5:
ALECT2 type Ia filament from renal biopsy tissue of an individual with ALECT2 amyloidosis
Method: EM (helical sym.) / Resolution: 1.96 Å

EMDB-66047, PDB-9wl6:
ALECT2 type Ib filament from renal biopsy tissue of an individual with ALECT2 amyloidosis
Method: EM (helical sym.) / Resolution: 1.95 Å

EMDB-66048, PDB-9wl7:
ALECT2 type IIa filament from renal biopsy tissue of an individual with ALECT2 amyloidosis
Method: EM (helical sym.) / Resolution: 2.93 Å

EMDB-66049, PDB-9wl8:
ALECT2 type IIb filament from renal biopsy tissue of an individual with ALECT2 amyloidosis
Method: EM (helical sym.) / Resolution: 3.09 Å

EMDB-66050, PDB-9wl9:
ALECT2 type III filament from renal biopsy tissue of an individual with ALECT2 amyloidosis
Method: EM (helical sym.) / Resolution: 3.05 Å

Source
  • homo sapiens (human)
KeywordsPROTEIN FIBRIL / Leukocyte chemotactic factor 2 amyloid filament

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