7nsl

Publication Abstract from PubMed

Systemic AL amyloidosis is a rare disease that is caused by the misfolding of immunoglobulin light chains (LCs). Potential drivers of amyloid formation in this disease are post-translational modifications (PTMs) and the mutational changes that are inserted into the LCs by somatic hypermutation. Here we present the cryo electron microscopy (cryo-EM) structure of an ex vivo lambda1-AL amyloid fibril whose deposits disrupt the ordered cardiomyocyte structure in the heart. The fibril protein contains six mutational changes compared to the germ line and three PTMs (disulfide bond, N-glycosylation and pyroglutamylation). Our data imply that the disulfide bond, glycosylation and mutational changes contribute to determining the fibril protein fold and help to generate a fibril morphology that is able to withstand proteolytic degradation inside the body.

Role of mutations and post-translational modifications in systemic AL amyloidosis studied by cryo-EM.,Radamaker L, Karimi-Farsijani S, Andreotti G, Baur J, Neumann M, Schreiner S, Berghaus N, Motika R, Haupt C, Walther P, Schmidt V, Huhn S, Hegenbart U, Schonland SO, Wiese S, Read C, Schmidt M, Fandrich M Nat Commun. 2021 Nov 5;12(1):6434. doi: 10.1038/s41467-021-26553-9. PMID:34741031^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.