title: Kinetic Insights into Zn2+-Induced Amyloid β-Protein Aggregation Revealed by Stopped-Flow Fluorescence Spectroscopy.
abstract: Zn2+has remarkable impacts on amyloid β-protein (Aβ) aggregation, which is crucial in the pathology of Alzheimer's disease. However, the Zn2+concentration in human cerebrospinal fluid is commonly too low for interaction with Aβ, and only during neurotransmission is there a transient release of a high concentration of Zn2+. It is difficult to explore the details of the interaction between Zn2+and Aβ within such a short time scale by using ordinary analytical methods. Herein, stopped-flow fluorescence spectroscopy was used to study the fast aggregation kinetics of Aβ42in the presence of Zn2+in the time scale from 1 ms to seconds. It was found that Zn2+bound to Aβ42within 1 ms; caused immediate conformational transition around Tyr10, which led to the enhancement of Aβ42hydrophobicity; and then promoted fast aggregation of Aβ42through enhanced hydrophobic interactions. Among the two Zn2+-binding sites on Aβ42(KD= 107 nM and 5.2 μM), the first one of higher affinity had a greater impact on the aggregation of Aβ42. Three kinetic phases were observed in the Zn2+-induced fast aggregation of Aβ42, and the fast phase was extremely accelerated by Zn2+, indicating that accelerated aggregation mainly occurred in the fast phase. The reactions occurring in this phase were closely related to the association of Zn2+and Aβ42. Moreover, Zn2+largely broadened the pH range of Aβ42fast aggregation from pH 5.2-6.2 without Zn2+to pH 5.2-7.8 in the presence of Zn2+. Besides, the promoting effect of Zn2+on Aβ42fast aggregation peaked at pH 6.8-7.8, which includes the pH values of the cerebrospinal fluid (pH 7.3) and hippocampus (pH 7.15-7.35). The findings demonstrate the significant effect of Zn2+on Aβ aggregation and provide new insight into its mechanisms.
authors.affiliation: Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University , Tianjin 300072, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University , Tianjin 300072, China.
authors.forename: Linling
authors.identifier: 0000-0002-8263-7595
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University , Tianjin 300072, China.
authors.forename: Yan
authors.identifier: 0000-0001-5256-9571
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University , Tianjin 300072, China.
authors.forename: Xiaoyan
authors.identifier: 0000-0002-8040-5897
authors.initials: X
authors.lastname: Dong
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000378:metabolism*; D011485:Protein Binding; D013050:Spectrometry, Fluorescence; D015032:Zinc / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D066329:Protein Aggregates; C075222:amyloid beta-protein (1-42); D015032:Zinc