VLITL is a major cross-beta-sheet signal for fibrinogen A alpha-chain frameshift variants
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.
Keywords
Amino Acid Sequence
fibrinogen A
polypeptide
unclassified drug
genetics
familial amyloidosis
transmission electron microscopy
human tissue
physiology
protein motif
Amino Acid Motifs
pathology
VLITL peptide
fibrinogen Aalpha
Article
beta sheet
computer model
fibril
fibrinogen A alpha chain amyloidoisis
genetic analysis
genetic variability
histology
in vitro study
kidney amyloidosis
kidney biopsy
in vivo study
laser microdissection
liquid chromatography-mass spectrometry
priority journal
protein aggregation
proteomics
Amyloid
Amyloidosis
Familial
Fibrinogen
Frameshift Mutation
Humans
Kidney
Protein Conformation
beta-Strand
human
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