A novel hotspot of gelsolin instability triggers an alternative mechanism of amyloid aggregation
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 gelsoli...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Elsevier
2021
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/28c0fa7cd36a48168031138ec41efe6d |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:28c0fa7cd36a48168031138ec41efe6d |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:28c0fa7cd36a48168031138ec41efe6d2021-12-04T04:33:33ZA novel hotspot of gelsolin instability triggers an alternative mechanism of amyloid aggregation2001-037010.1016/j.csbj.2021.11.025https://doaj.org/article/28c0fa7cd36a48168031138ec41efe6d2021-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2001037021004906https://doaj.org/toc/2001-0370Gelsolin 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 C. elegans-based assay. Our data suggest that aggregation of G4G5 variants follows an alternative, likely proteolysis-independent, pathway.Michela BollatiLuisa DiomedeToni GiorginoCarmina NataleElisa FagnaniIrene BoniardiAlberto BarbiroliRebecca AlemaniMarten BeegMarco GobbiAna FakinEloise MastrangeloMario MilaniGianluca PresciuttiniEdi GabellieriPatrizia CioniMatteo de RosaElsevierarticleAmyloidosisC. elegansGelsolinMisfoldingPathogenic variantBiotechnologyTP248.13-248.65ENComputational and Structural Biotechnology Journal, Vol 19, Iss , Pp 6355-6365 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Amyloidosis C. elegans Gelsolin Misfolding Pathogenic variant Biotechnology TP248.13-248.65 |
| spellingShingle |
Amyloidosis C. elegans Gelsolin Misfolding Pathogenic variant Biotechnology TP248.13-248.65 Michela Bollati Luisa Diomede Toni Giorgino Carmina Natale Elisa Fagnani Irene Boniardi Alberto Barbiroli Rebecca Alemani Marten Beeg Marco Gobbi Ana Fakin Eloise Mastrangelo Mario Milani Gianluca Presciuttini Edi Gabellieri Patrizia Cioni Matteo de Rosa A novel hotspot of gelsolin instability triggers an alternative mechanism of amyloid aggregation |
| description |
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 C. elegans-based assay. Our data suggest that aggregation of G4G5 variants follows an alternative, likely proteolysis-independent, pathway. |
| format |
article |
| author |
Michela Bollati Luisa Diomede Toni Giorgino Carmina Natale Elisa Fagnani Irene Boniardi Alberto Barbiroli Rebecca Alemani Marten Beeg Marco Gobbi Ana Fakin Eloise Mastrangelo Mario Milani Gianluca Presciuttini Edi Gabellieri Patrizia Cioni Matteo de Rosa |
| author_facet |
Michela Bollati Luisa Diomede Toni Giorgino Carmina Natale Elisa Fagnani Irene Boniardi Alberto Barbiroli Rebecca Alemani Marten Beeg Marco Gobbi Ana Fakin Eloise Mastrangelo Mario Milani Gianluca Presciuttini Edi Gabellieri Patrizia Cioni Matteo de Rosa |
| author_sort |
Michela Bollati |
| title |
A novel hotspot of gelsolin instability triggers an alternative mechanism of amyloid aggregation |
| title_short |
A novel hotspot of gelsolin instability triggers an alternative mechanism of amyloid aggregation |
| title_full |
A novel hotspot of gelsolin instability triggers an alternative mechanism of amyloid aggregation |
| title_fullStr |
A novel hotspot of gelsolin instability triggers an alternative mechanism of amyloid aggregation |
| title_full_unstemmed |
A novel hotspot of gelsolin instability triggers an alternative mechanism of amyloid aggregation |
| title_sort |
novel hotspot of gelsolin instability triggers an alternative mechanism of amyloid aggregation |
| publisher |
Elsevier |
| publishDate |
2021 |
| url |
https://doaj.org/article/28c0fa7cd36a48168031138ec41efe6d |
| work_keys_str_mv |
AT michelabollati anovelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT luisadiomede anovelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT tonigiorgino anovelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT carminanatale anovelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT elisafagnani anovelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT ireneboniardi anovelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT albertobarbiroli anovelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT rebeccaalemani anovelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT martenbeeg anovelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT marcogobbi anovelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT anafakin anovelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT eloisemastrangelo anovelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT mariomilani anovelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT gianlucapresciuttini anovelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT edigabellieri anovelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT patriziacioni anovelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT matteoderosa anovelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT michelabollati novelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT luisadiomede novelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT tonigiorgino novelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT carminanatale novelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT elisafagnani novelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT ireneboniardi novelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT albertobarbiroli novelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT rebeccaalemani novelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT martenbeeg novelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT marcogobbi novelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT anafakin novelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT eloisemastrangelo novelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT mariomilani novelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT gianlucapresciuttini novelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT edigabellieri novelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT patriziacioni novelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation AT matteoderosa novelhotspotofgelsolininstabilitytriggersanalternativemechanismofamyloidaggregation |
| _version_ |
1718372958706073600 |