8HGA
Monomer structure of transforming growth factor beta induced protein (TGFBIp) G623R fibril
Summary for 8HGA
| Entry DOI | 10.2210/pdb8hga/pdb |
| Descriptor | Transforming growth factor-beta-induced protein ig-h3 (1 entity in total) |
| Functional Keywords | pathological fibrils, tgfbi related corneal dystrophy, protein fibril |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 10191.69 |
| Authors | Low, J.Y.K.,Pervushin, K. (deposition date: 2022-11-14, release date: 2023-07-26, Last modification date: 2024-05-15) |
| Primary citation | Low, J.Y.K.,Shi, X.,Anandalakshmi, V.,Neo, D.,Peh, G.S.L.,Koh, S.K.,Zhou, L.,Abdul Rahim, M.K.,Boo, K.,Lee, J.,Mohanram, H.,Alag, R.,Mu, Y.,Mehta, J.S.,Pervushin, K. Release of frustration drives corneal amyloid disaggregation by brain chaperone. Commun Biol, 6:348-348, 2023 Cited by PubMed Abstract: 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. PubMed: 36997596DOI: 10.1038/s42003-023-04725-1 PDB entries with the same primary citation |
| Experimental method | SOLID-STATE NMR |
Structure validation
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