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An electrostatic cluster guides Aß40 fibril formation in sporadic and Dutch-type cerebral amyloid angiopathy.
Fu, Ziao; Crooks, Elliot J; Irizarry, Brandon A; Zhu, Xiaoyue; Chowdhury, Saikat; Van Nostrand, William E; Smith, Steven O.
Afiliação
  • Fu Z; Center for Structural Biology, Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794-5215, United States; Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller University, New York, NY 10065, United States.
  • Crooks EJ; Center for Structural Biology, Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794-5215, United States.
  • Irizarry BA; Center for Structural Biology, Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794-5215, United States.
  • Zhu X; George and Anne Ryan Institute for Neuroscience, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, United States.
  • Chowdhury S; Center for Structural Biology, Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794-5215, United States; CSIR-Centre for Cellular & Molecular Biology, Habsiguda, Uppal Road, Hyderabad 500 007, Telangana, India; Academy of Scientific and Innovative Research (
  • Van Nostrand WE; George and Anne Ryan Institute for Neuroscience, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, United States. Electronic address: wvannostrand@uri.edu.
  • Smith SO; Center for Structural Biology, Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794-5215, United States.
J Struct Biol ; 216(2): 108092, 2024 Jun.
Article em En | MEDLINE | ID: mdl-38615725
ABSTRACT
Cerebral amyloid angiopathy (CAA) is associated with the accumulation of fibrillar Aß peptides upon and within the cerebral vasculature, which leads to loss of vascular integrity and contributes to disease progression in Alzheimer's disease (AD). We investigate the structure of human-derived Aß40 fibrils obtained from patients diagnosed with sporadic or familial Dutch-type (E22Q) CAA. Using cryo-EM, two primary structures are identified containing elements that have not been observed in in vitro Aß40 fibril structures. One population has an ordered N-terminal fold comprised of two ß-strands stabilized by electrostatic interactions involving D1, E22, D23 and K28. This charged cluster is disrupted in the second population, which exhibits a disordered N-terminus and is favored in fibrils derived from the familial Dutch-type CAA patient. These results illustrate differences between human-derived CAA and AD fibrils, and how familial CAA mutations can guide fibril formation.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Peptídeos beta-Amiloides / Angiopatia Amiloide Cerebral / Eletricidade Estática Limite: Humans Idioma: En Revista: J Struct Biol Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Peptídeos beta-Amiloides / Angiopatia Amiloide Cerebral / Eletricidade Estática Limite: Humans Idioma: En Revista: J Struct Biol Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos