دورية أكاديمية
أعرض في EDS

Role of Hydrophobicity at the N-Terminal Region of Aβ42 in Secondary Nucleation.

التفاصيل البيبلوغرافية
العنوان: Role of Hydrophobicity at the N-Terminal Region of Aβ42 in Secondary Nucleation.
المؤلفون: Thacker D; Department of Biochemistry and Structural Biology, Lund University, Lund22362, Sweden., Willas A; Department of Biochemistry and Structural Biology, Lund University, Lund22362, Sweden., Dear AJ; Department of Biochemistry and Structural Biology, Lund University, Lund22362, Sweden.; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K., Linse S; Department of Biochemistry and Structural Biology, Lund University, Lund22362, Sweden.
المصدر: ACS chemical neuroscience [ACS Chem Neurosci] 2022 Dec 07; Vol. 13 (23), pp. 3477-3487. Date of Electronic Publication: 2022 Nov 21.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 101525337 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1948-7193 (Electronic) Linking ISSN: 19487193 NLM ISO Abbreviation: ACS Chem Neurosci Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, D.C. : American Chemical Society
مواضيع طبية MeSH: Amyloid beta-Peptides*/genetics
مستخلص: The self-assembly of the amyloid β 42 (Aβ42) peptide is linked to Alzheimer's disease, and oligomeric intermediates are linked to neuronal cell death during the pathology of the disease. These oligomers are produced prolifically during secondary nucleation, by which the aggregation of monomers is catalyzed on fibril surfaces. Significant progress has been made in understanding the aggregation mechanism of Aβ42; still, a detailed molecular-level understanding of secondary nucleation is lacking. Here, we explore the role of four hydrophobic residues on the unstructured N-terminal region of Aβ42 in secondary nucleation. We create eight mutants with single substitutions at one of the four positions─Ala2, Phe4, Tyr10, and Val12─to decrease the hydrophobicity at respective positions (A2T, A2S, F4A, F4S, Y10A, Y10S, V12A, and V12S) and one mutant (Y10F) to remove the polar nature of Tyr10. Kinetic analyses of aggregation data reveal that the hydrophobicity at the N-terminal region of Aβ42, especially at positions 10 and 12, affects the rate of fibril mass generated via secondary nucleation. Cryo-electron micrographs reveal that most of the mutants with lower hydrophobicity form fibrils that are markedly longer than WT Aβ42, in line with the reduced secondary nucleation rates for these peptides. The dominance of secondary nucleation, however, is still retained in the aggregation mechanism of these mutants because the rate of primary nucleation is even more reduced. This highlights that secondary nucleation is a general phenomenon that is not dependent on any one particular feature of the peptide and is rather robust to sequence perturbations.
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فهرسة مساهمة: Keywords: Alzheimer’s disease; amyloid; hydrophobicity; secondary nucleation
المشرفين على المادة: 0 (Amyloid beta-Peptides)
تواريخ الأحداث: Date Created: 20221121 Date Completed: 20221215 Latest Revision: 20230119
رمز التحديث: 20230120
مُعرف محوري في PubMed: PMC9732875
DOI: 10.1021/acschemneuro.2c00504
PMID: 36411082
قاعدة البيانات: MEDLINE
الوصف
تدمد:1948-7193
DOI:10.1021/acschemneuro.2c00504