Cryo-EM structure of cardiac amyloid fibrils from an immunoglobulin light chain AL amyloidosis patient

Abstract

Systemic light chain amyloidosis (AL) is a life-threatening disease caused by aggregation and deposition of monoclonal immunoglobulin light chains (LC) in target organs. Severity of heart involvement is the most important factor determining prognosis. Here, we report the 4.0 Å resolution cryo-electron microscopy map and molecular model of amyloid fibrils extracted from the heart of an AL amyloidosis patient with severe amyloid cardiomyopathy. The helical fibrils are composed of a single protofilament, showing typical 4.9 Å stacking and cross-β architecture. Two distinct polypeptide stretches (total of 77 residues) from the LC variable domain (Vl) fit the fibril density. Despite Vl high sequence variability, residues stabilizing the fibril core are conserved through different cardiotoxic Vl, highlighting structural motifs that may be common to misfolding-prone LCs. Our data shed light on the architecture of LC amyloids, correlate amino acid sequences with fibril assembly, providing the grounds for development of innovative medicines.

Half a century of amyloids: past, present and future

“…355 Precisely 60 years after Cohen and Calkins revealed, with electron microscopy, the presence of fibrils in the tissue, 53 cryoTEM structures became available for amyloid fibrils that were purified from the tissue of patients affected by systemic AA, AL or ATTR amyloidosis. 120,[361][362][363] These structures revealed that the fibril protein folds are, in all cases, substantially different from their conformation in the respective native proteins. The implication of this observation is that the conformation of the native state has to be almost entirely unfolded in order to enable the reorganization of the polypeptide chain into the fibril protein fold.…”

“…362 The fibrils that can be extracted from a patient or animal are typically polymorphic with one dominating fibril morphology. 120,[361][362][363][364] Consistent fibril morphologies are deposited at different sites/organs of the same patient or animal 365 and even in different patients or animals, as long as they belong to the same subtype of systemic amyloidosis and possess the same sequence of the fibril precursor protein. 119,362,365 Current ways of treatment of systemic amyloidosis are mostly focused on a reduction of the fibril precursor protein.…”

Prion protein—Semisynthetic prion protein (PrP) variants with posttranslational modifications

“…The structure of the infectious PrP rods differentiates them from all other protein assemblies so far studied in neurodegenerative diseases. This includes characterizations by cryo‐EM of tau filaments from AD and monoclonal immunoglobulin light chain (LC) fibrils from amyloid light‐chain (AL) amyloidosis . To date, cryo‐EM studies of tau and AL represent the only structural data of fibrils directly extracted from human tissue under pathologic conditions.…”

“…84,85 Caughey and coworkers [86][87][88] amyloidosis. 90 To date, cryo-EM studies of tau and AL represent the only structural data of fibrils directly extracted from human tissue under pathologic conditions. For tau-paired helical and straight filaments could be identified with cores made of two identical protofilaments that adopt a combined cross-β/β-helix structure.…”

Amyloid structure determination in RELION-3.1

“…We used this implementation to solve the first cryo-EM structures of amyloid filaments to sufficient resolution to build de novo atomic models: the paired helical and straight filaments (PHFs and SFs) that are formed by the tau protein in Alzheimer's disease (Fitzpatrick et al, 2017). Since then, this approach in RELION has been used to solve multiple cryo-EM structures of amyloids, for example from tau Falcon, Zhang, Schweighauser et al, 2018;Falcon et al, 2019;Zhang et al, 2019), -synuclein (Li, Zhao et al, 2018;Li, Ge et al, 2018;Guerrero-Ferreira et al, 2018Boyer et al, 2019), 2 -microglobulin (Iadanza et al, 2018), amyloid protein A and amyloid light chain from systemic amyloidosis (Liberta et al, 2019;Swuec et al, 2019;Radamaker et al, 2019), TDP-43 (Cao et al, 2019) and amyloid- (Kollmer et al, 2019).…”