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Role of mutations and post-translational modifications in systemic AL amyloidosis studied by cryo-EM.

Lynn RadamakerSara Karimi-FarsijaniGiada AndreottiJulian BaurMatthias NeumannSarah SchreinerNatalie BerghausRaoul MotikaChristian HauptPaul WaltherVolker SchmidtStefanie HuhnUte HegenbartStefan O SchönlandSebastian WieseClarissa ReadMatthias SchmidtMarcus Fändrich
Published in: Nature communications (2021)
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 λ1-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.
Keyphrases
  • electron microscopy
  • protein protein
  • heart failure
  • binding protein
  • high resolution
  • electronic health record
  • small molecule
  • dna methylation
  • risk assessment
  • machine learning
  • high glucose
  • genome wide