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VLITL is a major cross-β-sheet signal for fibrinogen Aα-chain frameshift variants

Cyrille Garnier, Fatma Briki, Brigitte Nedelec, Patrick Le Pogamp, Ahmet Dogan, Nathalie Rioux-Leclercq, Renan Goude, Caroline Beugnet, Laurent Martin, Marc Delpech, Franck Bridoux, Gilles Grateau, Jean Doucet, Philippe Derreumaux and Sophie Valleix

Key points

  • VLITL is amyloid-prone and forms the ends of Aα-chain fibrils in vivo.

  • VLITL explains the molecular basis of Aα-chain amyloidogenesis.

Abstract

The first case of hereditary fibrinogen Aα-chain amyloidosis was recognized more than 20 years ago, but disease mechanisms still remain unknown. Here we report detailed clinical and proteomics studies of a French kindred with a novel amyloidogenic fibrinogen Aα-chain frameshift variant, Phe521Leufs, causing a severe familial form of renal amyloidosis. Next, we focused our investigations to elucidate the molecular basis that render this Aα-chain variant amyloidogenic. We show that a 49-mer peptide derived from the C-terminal part of the Phe521Leufs-chain is deposited as fibrils in the patient's kidneys, establishing that only a small portion of Phe521Leufs directly contributes to amyloid formation in vivo. In silico analysis indicated that this 49-mer Aα-chain peptide contained a motif (VLITL), with a high intrinsic propensity for β-aggregation at residues 44-48 of human renal fibrils. To experimentally verify the amyloid propensity of VLITL, we generated synthetic Phe521Leufs-derived peptides and compared their capacity for fibril formation in vitro with that of their VLITL-deleted counterparts. We show that VLITL forms typical amyloid fibrils in vitro and is a major signal for cross-β-sheet self-association of the 49-mer Phe521Leufs-peptide identified in vivo, while its absence abrogates fibril formation. This study provides compelling evidence that VLITL confers amyloidogenic properties to Aα-chain frameshift variants, yielding a previously unknown molecular basis for the pathogenesis of Aα-chain amyloidosis.

  • Submitted July 13, 2017.
  • Accepted October 24, 2017.