Hoop, CL, Zhu, J, Bhattacharya, S et al. (3 more authors) (2020) Collagen I weakly interacts with the β-sheets of β2-microglobulin and enhances conformational exchange to induce amyloid formation. Journal of the American Chemical Society, 142 (3). pp. 1321-1331. ISSN 0002-7863
Abstract
Amyloidogenesis is significant in both protein function and pathology. Amyloid formation of folded, globular proteins is commonly initiated by partial or complete unfolding. However, how this unfolding event is triggered for proteins that are otherwise stable in their native environments is not well understood. The accumulation of the immunoglobulin protein β2-microglobulin (β2m) into amyloid plaques in the joints of long-term hemodialysis patients is the hallmark of Dialysis Related Amyloidosis (DRA). While β2m does not form amyloid unassisted near neutral pH in vitro, the localization of β2m deposits to joint spaces suggests a role for the local extracellular matrix (ECM) proteins, specifically collagens, in promoting amyloid formation. Indeed, collagen and other ECM components have been observed to facilitate β2m amyloid formation, but the large size and anisotropy of the complex, combined with the low affinity of these interactions, has limited atomic-level elucidation of the amyloid-promoting mechanism(s) by these molecules. Using solution NMR approaches that uniquely probe weak interactions in large molecular weight complexes, we are able to map the binding interfaces on β2m for collagen I and detect collagen I-induced μs–ms timescale dynamics in the β2m backbone. By combining solution NMR relaxation methods and 15N-dark state exchange saturation transfer experiments, we propose a model in which weak, multimodal collagen I–β2m interactions promote exchange with a minor population of amyloid-competent species to induce fibrillogenesis. The results portray the intimate role of the environment in switching an innocuous protein into an amyloid-competent state, rationalizing the localization of amyloid deposits in DRA.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2019 American Chemical Society. This is an author produced version of an article published in Journal of the American Chemical Society. Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Structural Molecular Biology (Leeds) |
Funding Information: | Funder Grant number Wellcome Trust 092896/Z/10/Z |
Depositing User: | Symplectic Publications |
Date Deposited: | 08 Jan 2020 12:14 |
Last Modified: | 25 Dec 2020 01:38 |
Status: | Published |
Publisher: | American Chemical Society |
Identification Number: | 10.1021/jacs.9b10421 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:155372 |