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A novel hotspot of gelsolin instability triggers an alternative mechanism of amyloid aggregation

DOI: 10.1016/j.csbj.2021.11.025 DOI Help

Authors: Michela Bollati (Consiglio Nazionale delle Ricerche) , Luisa Diomede (Istituto di Ricerche Farmacologiche Mario Negri IRCCS) , Toni Giorgino (Consiglio Nazionale delle Ricerche) , Carmina Natale (Istituto di Ricerche Farmacologiche Mario Negri IRCCS) , Elisa Fagnani (Consiglio Nazionale delle Ricerche) , Irene Boniardi (Consiglio Nazionale delle Ricerche) , Alberto Barbiroli (Università degli Studi di Milano) , Rebecca Alemani (Consiglio Nazionale delle Ricerche) , Marten Beeg (Istituto di Ricerche Farmacologiche Mario Negri IRCCS) , Marco Gobbi (Istituto di Ricerche Farmacologiche Mario Negri IRCCS) , Ana Fakin (University Medical Centre Ljubljana) , Eloise Mastrangelo (Consiglio Nazionale delle Ricerche) , Mario Milani (Consiglio Nazionale delle Ricerche) , Gianluca Presciuttini (Consiglio Nazionale delle Ricerche) , Edi Gabellieri (Consiglio Nazionale delle Ricerche) , Patrizia Cioni (Consiglio Nazionale delle Ricerche) , Matteo De Rosa (Consiglio Nazionale delle Ricerche)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Computational And Structural Biotechnology Journal , VOL 281

State: Published (Approved)
Published: November 2021
Diamond Proposal Number(s): 20221

Open Access Open Access

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: ╬▓-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 C. elegans-based assay. Our data suggest that aggregation of G4G5 variants follows an alternative, likely proteolysis-independent, pathway.

Journal Keywords: Amyloidosis; C. elegans; Gelsolin; Misfolding; Pathogenic Variant

Diamond Keywords: Amyloidosis

Subject Areas: Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography

Added On: 23/11/2021 10:44

Documents:
1-s2.0-S2001037021004906-main.pdf

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)