Release of frustration drives corneal amyloid disaggregation by brain chaperone.
Jia Yi Kimberly LowXiangyan ShiVenkatraman AnandalakshmiDawn NeoGary Swee Lim PehSiew Kwan KohLei ZhouM K Abdul RahimKetti BooJiaXuan LeeHarini MohanramReema AlagYuguang MuJodhbir S MehtaKonstantin PervushinPublished in: Communications biology (2023)
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.
Keyphrases
- heat shock
- optical coherence tomography
- wound healing
- heat shock protein
- cataract surgery
- end stage renal disease
- newly diagnosed
- magnetic resonance
- ejection fraction
- multiple sclerosis
- endothelial cells
- peritoneal dialysis
- white matter
- amino acid
- high resolution
- resting state
- small molecule
- patient reported outcomes
- brain injury
- patient reported
- blood brain barrier