8FRR
Wild-type myocilin olfactomedin domain
Summary for 8FRR
| Entry DOI | 10.2210/pdb8frr/pdb |
| Descriptor | Myocilin, C-terminal fragment, GLYCEROL, CALCIUM ION, ... (5 entities in total) |
| Functional Keywords | myocilin, olfactomedin, glaucoma, beta-propeller, protein binding |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 29411.99 |
| Authors | Ma, M.T.,Lieberman, R.L.,Huard, D.J.E. (deposition date: 2023-01-08, release date: 2024-01-17, Last modification date: 2024-10-09) |
| Primary citation | Saccuzzo, E.G.,Mebrat, M.D.,Scelsi, H.F.,Kim, M.,Ma, M.T.,Su, X.,Hill, S.E.,Rheaume, E.,Li, R.,Torres, M.P.,Gumbart, J.C.,Van Horn, W.D.,Lieberman, R.L. Competition between inside-out unfolding and pathogenic aggregation in an amyloid-forming beta-propeller. Nat Commun, 15:155-155, 2024 Cited by PubMed Abstract: Studies of folded-to-misfolded transitions using model protein systems reveal a range of unfolding needed for exposure of amyloid-prone regions for subsequent fibrillization. Here, we probe the relationship between unfolding and aggregation for glaucoma-associated myocilin. Mutations within the olfactomedin domain of myocilin (OLF) cause a gain-of-function, namely cytotoxic intracellular aggregation, which hastens disease progression. Aggregation by wild-type OLF (OLF) competes with its chemical unfolding, but only below the threshold where OLF loses tertiary structure. Representative moderate (OLF) and severe (OLF) disease variants aggregate differently, with rates comparable to OLF in initial stages of unfolding, and variants adopt distinct partially folded structures seen along the OLF urea-unfolding pathway. Whether initiated with mutation or chemical perturbation, unfolding propagates outward to the propeller surface. In sum, for this large protein prone to amyloid formation, the requirement for a conformational change to promote amyloid fibrillization leads to direct competition between unfolding and aggregation. PubMed: 38168102DOI: 10.1038/s41467-023-44479-2 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.27 Å) |
Structure validation
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