VLITL is a major cross-β-sheet signal for fibrinogen Aα-chain frameshift variants VLITL explains the molecular basis of Aα-chain amyloidogenesis

• Published in: Blood Vol. 130; no. 25; pp. 2799 - 2807
• Main Authors: Garnier, Cyrille, Briki, Fatma, Nedelec, Brigitte, Le Pogamp, Patrick, Dogan, Ahmet, Rioux-Leclercq, Nathalie, Goude, Renan, Beugnet, Caroline, Martin, Laurent, Delpech, Marc, Bridoux, Frank, Grateau, Gilles, Doucet, Jean, Derreumaux, Philippe, Valleix, Sophie
• Format: Journal Article
• Language: English
• Published: American Society of Hematology 21-12-2017
• Subjects: Life Sciences; 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
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2017-07-796185

The first case of hereditary fibrinogen A alpha-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 A alpha-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 A alpha-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 A alpha-chain peptide contained a motif (VLITL), with a high intrinsic propensity for beta-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-beta-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 A alpha-chain frameshift variants, yielding a previously unknown molecular basis for the pathogenesis of A alpha-chain amyloidosis.