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

Lynn Radamaker,Stefanie Huhn,Yin-Hsi Lin,Ute Hegenbart,Karthikeyan Annamalai,Günter Fritz,Marcus Fändrich,Matthias Schmidt,Stefan O Schönland

doi:10.1038/s41467-019-09032-0

Lynn Radamaker, Stefanie Huhn + Show 7 more

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https://doi.org/10.1038/s41467-019-09032-0

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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.

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Amyloid fibrils derived from antibody light chains are key pathogenic agents in systemic AL amyloidosis
Using negatively stained transmission electron microscopy (TEM), we recently demonstrated that the fibrils from this patient contain a dominant fibril morphology, exhibiting a width of 13.6 ± 0.9 nm, and a minor morphology with a width of 20.4 ± 0.4 nm[23]
The fibrils are derived from the germ line segments IGLV1-44, IGLJ3, and IGLC2, demonstrating that the fibrils are representative for a λ-subtype causing cardiac involvement

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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. Our structure provides insight into the mechanism of protein misfolding and the role of patient-specific mutations in pathogenicity. 1234567890():,; Antibodies are protein structures of utmost importance to human health. They underlie the humoral immune system and many top-selling biopharmaceutical agents; yet, they can be the basis of devastating human diseases with systemic. The misfolding of immunoglobulin light chains (LCs), which are constituents of natural antibodies[5], gives rise to the disease

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