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, Frank Bridoux, Gilles Grateau, Jean Doucet, Philippe Derreumaux, Sophie Valleix

Journal: Blood 2018;130(25):2799-2807

PMID: 29089309

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Abstract

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.

Address: Mécanismes Moléculaires dans les Démences Neurodégénératives INSERM U1198, Université Montpellier, Montpellier, France.; Laboratoire de Physique des Solides, Université Paris Sud, Orsay, France.; Institut National de la Santé et de la Recherche Médicale, Unité mixte de Recherche U_1163, Institut IMAGINE, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.; Service de Néphrologie, CHU de Rennes, Rennes, France.; Division of Anatomic Pathology, Mayo Clinic, Rochester, MN.; Department of Laboratory Medicine and Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.; Département d'Anatomie et Cytologie Pathologiques, Centre Hospitalo-Universitaire Pontchaillou, et CNRS/UMR6061, IFR140, Faculté de Médecine, Université de Rennes 1, Rennes, France.; Institut de Génétique et Développement de Rennes, Unité Mixte de Recherche 6290, Centre National de la Recherche Scientifique, Rennes, France.; Laboratoire de Génétique Moléculaire, Hôpital Necker-Enfants Malades, Paris, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris, AP-HP, Paris, France.; Service d'Anatomie Pathologique, Faculté de Médecine de Dijon, Dijon, France.; Laboratoire de Biochimie et Génétique Moléculaire, Hôpital Cochin, Paris, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris, AP-HP, Paris, France.; Service de Néphrologie, CHU de Poitiers, et Centre national de référence des amyloses AL et autres maladies de dépôts d'immunoglobulines monoclonales, Poitiers, France.; Service de Médecine Interne, Hôpital Tenon, Paris, et Centre de référence des amyloses d'origine inflammatoire et de la fièvre méditerranéenne familiale, Paris, France; and.; Laboratoire de Biochimie Théorique, UPR9080 CNRS, Université Denis Diderot, Sorbonne Paris Cité, IBPC, Institut Universitaire de France, Paris, France.

DOI: 10.1182/blood-2017-07-796185

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MeSH Terms: Amino Acid Motifs, Amino Acid Sequence, Amyloid, Amyloidosis, Familial, Fibrinogen, Frameshift Mutation, Humans, Kidney, Protein Conformation, beta-Strand