8ORL
Crystal structure of the S23226G missense variant of titin domain Fn3-56
Summary for 8ORL
| Entry DOI | 10.2210/pdb8orl/pdb |
| Related | 4o00 8OIY 8OMW 8OQ9 |
| Descriptor | Titin, ZINC ION, CHLORIDE ION, ... (4 entities in total) |
| Functional Keywords | titin fibronectin type iii a-band structural protein, structural protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 3 |
| Total formula weight | 34544.25 |
| Authors | Rees, M.,Gautel, M. (deposition date: 2023-04-14, release date: 2023-08-23, Last modification date: 2023-08-30) |
| Primary citation | Rees, M.,Nikoopour, R.,Alexandrovich, A.,Pfuhl, M.,Lopes, L.R.,Akhtar, M.M.,Syrris, P.,Elliott, P.,Carr-White, G.,Gautel, M. Structure determination and analysis of titin A-band fibronectin type III domains provides insights for disease-linked variants and protein oligomerisation. J.Struct.Biol., 215:108009-108009, 2023 Cited by PubMed Abstract: Titin is the largest protein found in nature and spans half a sarcomere in vertebrate striated muscle. The protein has multiple functions, including in the organisation of the thick filament and acting as a molecular spring during the muscle contraction cycle. Missense variants in titin have been linked to both cardiac and skeletal myopathies. Titin is primarily composed of tandem repeats of immunoglobulin and fibronectin type III (Fn3) domains in a variety of repeat patterns; however, the vast majority of these domains have not had their high-resolution structure determined experimentally. Here, we present the crystal structures of seven wild type titin Fn3 domains and two harbouring rare missense variants reported in hypertrophic cardiomyopathy (HCM) patients. All domains present the typical Fn3 fold, with the domains harbouring variants reported in HCM patients retaining the wild-type conformation. The effect on domain folding and stability were assessed for five rare missense variants found in HCM patients: four caused thermal destabilization of between 7 and 13 °C and one prevented the folding of its domain. The structures also allowed us to locate the positions of residues whose mutations have been linked to congenital myopathies and rationalise how they convey their deleterious effects. We find no evidence of physiological homodimer formation, excluding one hypothesised mechanism as to how titin variants could exert pathological effects. PubMed: 37549721DOI: 10.1016/j.jsb.2023.108009 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.43 Å) |
Structure validation
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