7P2B
Crystal structure of human gelsolin amyloid mutant A551P
Summary for 7P2B
| Entry DOI | 10.2210/pdb7p2b/pdb |
| Descriptor | Gelsolin, SULFATE ION, GLYCEROL, ... (5 entities in total) |
| Functional Keywords | gelsolin protein, actin binding protein, structural protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 172532.10 |
| Authors | Bollati, M.,de Rosa, M. (deposition date: 2021-07-05, release date: 2022-05-18, Last modification date: 2024-10-16) |
| Primary citation | Bollati, M.,Diomede, L.,Giorgino, T.,Natale, C.,Fagnani, E.,Boniardi, I.,Barbiroli, A.,Alemani, R.,Beeg, M.,Gobbi, M.,Fakin, A.,Mastrangelo, E.,Milani, M.,Presciuttini, G.,Gabellieri, E.,Cioni, P.,de Rosa, M. A novel hotspot of gelsolin instability triggers an alternative mechanism of amyloid aggregation. Comput Struct Biotechnol J, 19:6355-6365, 2021 Cited by PubMed Abstract: Gelsolin comprises six homologous domains, named G1 to G6. Single point substitutions in this protein are responsible for AGel amyloidosis, a hereditary disease causing progressive corneal lattice dystrophy, cutis laxa, and polyneuropathy. Although several different amyloidogenic variants of gelsolin have been identified, only the most common mutants present in the G2 domain have been thoroughly characterized, leading to clarification of the functional mechanism. The molecular events underlying the pathological aggregation of 3 recently identified mutations, namely A551P, E553K and M517R, all localized at the interface between G4 and G5, are here explored for the first time. Structural studies point to destabilization of the interface between G4 and G5 due to three structural determinants: β-strand breaking, steric hindrance and/or charge repulsion, all implying impairment of interdomain contacts. Such rearrangements decrease the temperature and pressure stability of gelsolin but do not alter its susceptibility to furin cleavage, the first event in the canonical aggregation pathway. These variants also have a greater tendency to aggregate in the unproteolysed forms and exhibit higher proteotoxicity in a -based assay. Our data suggest that aggregation of G4G5 variants follows an alternative, likely proteolysis-independent, pathway. PubMed: 34938411DOI: 10.1016/j.csbj.2021.11.025 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3 Å) |
Structure validation
Download full validation report
