Release of frustration drives corneal amyloid disaggregation by brain chaperone

Release of frustration drives corneal amyloid disaggregation by brain chaperone

TGFBI-related corneal dystrophy (CD) is characterized by the accumulation of insoluble protein deposits in the corneal tissues, eventually leading to progressive corneal opacity. Here we show that ATP-independent amyloid-β chaperone L-PGDS can effectively disaggregate corneal amyloids in surgically...

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Bibliographic Details
Published in:Communications biology Vol. 6; no. 1; p. 348
Main Authors: Low, Jia Yi Kimberly, Shi, Xiangyan, Anandalakshmi, Venkatraman, Neo, Dawn, Peh, Gary Swee Lim, Koh, Siew Kwan, Zhou, Lei, Abdul Rahim, M. K., Boo, Ketti, Lee, JiaXuan, Mohanram, Harini, Alag, Reema, Mu, Yuguang, Mehta, Jodhbir S., Pervushin, Konstantin
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 30-03-2023
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Subjects:
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Adenosine Triphosphate - metabolism
Alzheimer's disease
Amyloid - metabolism
Amyloid beta-Peptides - metabolism
Biology
Biomedical and Life Sciences
Brain - metabolism
Chaperones
Cornea
Cornea - metabolism
Corneal Dystrophies, Hereditary - metabolism
Corneal dystrophy
Disaggregation
Free energy
Frustration
Humans
Life Sciences
Molecular Chaperones - metabolism
Transforming Growth Factor beta - metabolism
β-Amyloid
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Summary:TGFBI-related corneal dystrophy (CD) is characterized by the accumulation of insoluble protein deposits in the corneal tissues, eventually leading to progressive corneal opacity. Here we show that ATP-independent amyloid-β chaperone L-PGDS can effectively disaggregate corneal amyloids in surgically excised human cornea of TGFBI-CD patients and release trapped amyloid hallmark proteins. Since the mechanism of amyloid disassembly by ATP-independent chaperones is unknown, we reconstructed atomic models of the amyloids self-assembled from TGFBIp-derived peptides and their complex with L-PGDS using cryo-EM and NMR. We show that L-PGDS specifically recognizes structurally frustrated regions in the amyloids and releases those frustrations. The released free energy increases the chaperone’s binding affinity to amyloids, resulting in local restructuring and breakage of amyloids to protofibrils. Our mechanistic model provides insights into the alternative source of energy utilized by ATP-independent disaggregases and highlights the possibility of using these chaperones as treatment strategies for different types of amyloid-related diseases. ATP-independent amyloid-β chaperone L-PGDS disaggregates corneal amyloids in surgically excised human cornea of TGFBI-related corneal dystrophy patients by recognizing and releasing structurally frustrated regions.
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ISSN:2399-3642
2399-3642
DOI:10.1038/s42003-023-04725-1