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The catalytic nature of protein aggregation.
| Content Provider | Europe PMC |
|---|---|
| Author | Dear, Alexander J. Meisl, Georg Michaels, Thomas C. T. Zimmermann, Manuela R. Linse, Sara Knowles, Tuomas P. J. |
| Copyright Year | 2020 |
| Description | The formation of amyloid fibrils from soluble peptide is a hallmark of many neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. Characterization of the microscopic reaction processes that underlie these phenomena have yielded insights into the progression of such diseases and may inform rational approaches for the design of drugs to halt them. Experimental evidence suggests that most of these reaction processes are intrinsically catalytic in nature and may display enzymelike saturation effects under conditions typical of biological systems, yet a unified modeling framework accounting for these saturation effects is still lacking. In this paper, we therefore present a universal kinetic model for biofilament formation in which every fundamental process in the reaction network can be catalytic. The single closed-form expression derived is capable of describing with high accuracy a wide range of mechanisms of biofilament formation and providing the first integrated rate law of a system in which multiple reaction processes are saturated. Moreover, its unprecedented mathematical simplicity permits us to very clearly interpret the effects of increasing saturation on the overall kinetics. The effectiveness of the model is illustrated by fitting it to the data of in vitro Aβ40 aggregation. Remarkably, we find that primary nucleation becomes saturated, demonstrating that it must be heterogeneous, occurring at interfaces and not in solution. |
| Abstract | The formation of amyloid fibrils from soluble peptide is a hallmark of manyneurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. Characterizationof the microscopic reaction processes that underlie these phenomena have yielded insightsinto the progression of such diseases and may inform rational approaches for the design ofdrugs to halt them. Experimental evidence suggests that most of these reaction processesare intrinsically catalytic in nature and may display enzymelike saturation effects underconditions typical of biological systems, yet a unified modeling framework accounting forthese saturation effects is still lacking. In this paper, we therefore present a universalkinetic model for biofilament formation in which every fundamental process in the reactionnetwork can be catalytic. The single closed-form expression derived is capable ofdescribing with high accuracy a wide range of mechanisms of biofilament formation andproviding the first integrated rate law of a system in which multiple reaction processesare saturated. Moreover, its unprecedented mathematical simplicity permits us to veryclearly interpret the effects of increasing saturation on the overall kinetics. Theeffectiveness of the model is illustrated by fitting it to the data of invitro Aβ40 aggregation. Remarkably, we find that primary nucleation becomessaturated, demonstrating that it must be heterogeneous, occurring at interfaces and not insolution. |
| Related Links | https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC7377910&blobtype=pdf |
| Page Count | 10 |
| ISSN | 00219606 |
| Volume Number | 152 |
| DOI | 10.1063/1.5133635 |
| PubMed Central reference number | PMC7377910 |
| Issue Number | 4 |
| PubMed reference number | 32007046 |
| Journal | The Journal of Chemical Physics [J Chem Phys] |
| e-ISSN | 10897690 |
| Language | English |
| Publisher | AIP Publishing LLC |
| Publisher Date | 2020-01-01 |
| Access Restriction | Open |
| Rights License | 0021-9606/2020/152(4)/045101/10/$0.00 © 2020 Author(s). |
| Content Type | Text |
| Resource Type | Article |
| Subject | Physics and Astronomy Medicine Physical and Theoretical Chemistry |
