TAILIEUCHUNG - Báo cáo Y học: BIGH3 (TGFBI) Arg124 mutations influence the amyloid conversion of related peptides in vitro Implications in the BIGH3-linked corneal dystrophies

Amyloid deposits with Arg124 mutated TGFBI protein havebeen identified inautosomal dominant blindingcorneal assessedin vitrothe mechanisms determin-ing TGFBI protein amyloid transformation involving mutations of peptides synthesized following the TGFBI protein sequence, centered on codon Arg124 holding the previously reported amyloidogenic mutations and the respective controls were andHis124 mutated peptide preparations contained significantly higher amounts of amyloid than the native peptide | Eur. J. Biochem. 269 5149-5156 2002 FEBS 2002 doi BIGH3 TGFBI Arg124 mutations influence the amyloid conversion of related peptides in vitro Implications in the BIGH3-linked corneal dystrophies Clair-Florent Schmitt-Bernard1 2 Alain Chavanieu3 Gudrun Herrada3 Guy Subra3 Bernard Arnaud4 Jacques G. Demaille1 Bernard Calas3 and Angel Argiles1 1Institut de Génétique Humaine CNRS UPR 1142 Montpellier France 2Antigone Ophtalmologie Montpellier France 3 Centre de Biochimie Structurale CNRS UMR 5048 Universite Montpellier Montpellier France 4Service d Ophtalmologie CMC Gui de Chauliac Montpellier France Amyloid deposits with Arg124 mutated TGFBI protein have been identified in autosomal dominant blinding corneal dystrophies. We assessed in vitro the mechanisms determining TGFBI protein amyloid transformation involving mutations of Arg124. Eight peptides snithesieed following the TGFBI protein sequence centered on codon Arg124 holding the previously reported amyloidogenic mutations and the respective controls were studied. Cys 124 and His 124 mutated peptide preparations contained significantly higher amounts of amyloid than the native peptide. Blocking the SH group of Cys124 and deleting the first four NH2-terminal amino acids including Val112-Val113 resulted in a decrease in amyloid fibril formation while deletion of the nine CONH2-terminal residues increased amyloid fibril concentration. Fourrier transformed- nlrared spedroscopy analysiís of the different peptide solutions showed an increase in b-pleated sheet structures in those with enhanced amyloid yielding. We detigned a pppilde BB1 iikely to counteract the role of Val112-Val113 in amyloid fibril formation. Incubation of Cys124 peptide with BB1 indeed resulted in a 35 inhibition of amyloid fibril formation. Our results are in Ceeping with the clinical observations of Arg124 mutation-linCed amyloidosis and show the importance of Val112-Val113 disulfide and hydrogen bonding in .

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