VLITL is a major cross-beta-sheet signal for fibrinogen A alpha-chain frameshift variants - Archive ouverte HAL Access content directly
Journal Articles Blood Year : 2017

VLITL is a major cross-beta-sheet signal for fibrinogen A alpha-chain frameshift variants

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Abstract

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.
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hal-01688181 , version 1 (24-04-2018)

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Cyrille Garnier, Fatma Briki, Brigitte Nedelec, Patrick Le Pogamp, Ahmet Dogan, et al.. VLITL is a major cross-beta-sheet signal for fibrinogen A alpha-chain frameshift variants. Blood, 2017, 130 (25), pp.2799-2807. ⟨10.1182/blood-2017-07-796185⟩. ⟨hal-01688181⟩
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