Fiche publication
Date publication
décembre 2017
Journal
Blood
Auteurs
Membres identifiés du Cancéropôle Est :
Pr MARTIN Laurent
Tous les auteurs :
Garnier C, Briki F, Nedelec B, Le Pogamp P, Dogan A, Rioux-Leclercq N, Goude R, Beugnet C, Martin L, Delpech M, Bridoux F, Grateau G, Doucet J, Derreumaux P, Valleix S
Lien Pubmed
Résumé
The first case of hereditary fibrinogen Aα-chain amyloidosis was recognized >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 to 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, whereas 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.
Mots clés
Amino Acid Motifs, physiology, Amino Acid Sequence, Amyloid, genetics, Amyloidosis, Familial, genetics, Fibrinogen, genetics, Frameshift Mutation, Humans, Kidney, pathology, Protein Conformation, beta-Strand
Référence
Blood. 2017 12 21;130(25):2799-2807
