Pathology

Disease

Amyloidosis

Amyloid β

Immunoglobulin light chain

Stereochemistry

Biology

Biophysics

Antibody

Inorganic chemistry

Chemistry

Immunology

Fibril

Amyloid (mycology)

AL amyloidosis

Amyloid fibril

Protein structure

Intramolecular force

Biochemistry

Medicine

Nature Communications

Amyloid fibrils derived from antibody light chains are key pathogenic agents in systemic AL amyloidosis. They can be deposited in multiple organs but cardiac amyloid is the major risk factor of mortality. Here we report the structure of a λ1 AL amyloid fibril from an explanted human heart at a resolution of 3.3 Å which we determined using cryo-electron microscopy. The fibril core consists of a 91-residue segment presenting an all-beta fold with ten mutagenic changes compared to the germ line. The conformation differs substantially from natively folded light chains: a rotational switch around the intramolecular disulphide bond being the crucial structural rearrangement underlying fibril formation. Our structure provides insight into the mechanism of protein misfolding and the role of patient-specific mutations in pathogenicity.

Cryo-EM structure of a light chain-derived amyloid fibril from a patient with systemic AL amyloidosis