@article {2017|2036, title = {VLITL is a major cross-β-sheet signal for fibrinogen Aα-chain frameshift variants.}, journal = {Blood}, volume = {130}, year = {2017}, month = {2017 12 21}, pages = {2799-2807}, 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\&$\#$39;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.

}, keywords = {Amino Acid Motifs, Amino Acid Sequence, Amyloid, Amyloidosis, Familial, Fibrinogen, Frameshift Mutation, Humans, Kidney, Protein Conformation, beta-Strand}, issn = {1528-0020}, doi = {10.1182/blood-2017-07-796185}, author = {Garnier, Cyrille and Briki, Fatma and Nedelec, Brigitte and Le Pogamp, Patrick and Dogan, Ahmet and Rioux-Leclercq, Nathalie and Goude, Renan and Beugnet, Caroline and Martin, Laurent and Delpech, Marc and Bridoux, Frank and Grateau, Gilles and Doucet, Jean and Philippe Derreumaux and Valleix, Sophie} } @article {2010, title = {The VLITL aggregation-prone motif might trigger amyloid fibril formation of fibrinogen A alpha-chain frameshift variants in vivo}, journal = {Amyloid-journal of Protein Folding Disorders}, volume = {17}, number = {Suppl. 1}, year = {2010}, note = {12th International Symposium on Amyloidosis from Molecular Mechanisms Toward the Cure of Systemic Amyloidoses, Rome, ITALY, APR 18-21, 2010}, pages = {96{\textendash}97}, author = {Valleix, S. and Philippe Derreumaux and Garnier, C. and Briki, F. and Boimard, M. and Doucet, J. and Rioux-Leclercq, N. and Martin, L. and Grateau, G. and Delpech, M. and Le Pogamp, P.} } @article {1995|1898, title = {A VIBRATIONAL MOLECULAR-FORCE FIELD OF MODEL COMPOUNDS WITH BIOLOGICAL INTEREST .4. PARAMETERS FOR THE DIFFERENT GLYCOSIDIC LINKAGES OF OLIGOSACCHARIDES}, journal = {J. Comput. Chem.}, volume = {16}, number = {2}, year = {1995}, month = {feb}, pages = {188{\textendash}199}, doi = {10.1002/jcc.540160206}, author = {Dauchez, M and Philippe Derreumaux and LAGANT, P and VERGOTEN, G} } @article {1993|1896, title = {VIBRATIONAL MOLECULAR-FORCE FIELD OF MODEL COMPOUNDS WITH BIOLOGIC INTEREST .2. HARMONIC DYNAMICS OF BOTH ANOMERS OF GLUCOSE IN THE CRYSTALLINE STATE}, journal = {J. Comput. Chem.}, volume = {14}, number = {3}, year = {1993}, month = {mar}, pages = {263{\textendash}277}, doi = {10.1002/jcc.540140303}, author = {Dauchez, M and Philippe Derreumaux and VERGOTEN, G} } @article {1990|1894, title = {A VIBRATIONAL MOLECULAR-FORCE FIELD OF MODEL COMPOUNDS WITH BIOLOGICAL INTEREST .1. HARMONIC DYNAMICS OF CRYSTALLINE UREA AT 123-K}, journal = {J. Comput. Chem.}, volume = {11}, number = {5}, year = {1990}, month = {jun}, pages = {560{\textendash}568}, doi = {10.1002/jcc.540110504}, author = {Philippe Derreumaux and VERGOTEN, G and LAGANT, P} }