SUMOylation of the brain-predominant Ataxin-3 isoform modulates its interaction with p97

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  • dc.contributor.author Almeida Cotrim, Brunoca
  • dc.contributor.author Abreu, Isabel A.ca
  • dc.contributor.author Matos, Carlos A.ca
  • dc.contributor.author Fraga, Joana F.ca
  • dc.contributor.author Fernandes, Saraca
  • dc.contributor.author Macedo, Maria G.ca
  • dc.contributor.author Gutiérrez Gallego, Ricardo, 1968-ca
  • dc.contributor.author Barbosa Pereira, Pedro Joséca
  • dc.contributor.author Carvalho, Ana Luísaca
  • dc.contributor.author Macedo Ribeiro, Sandraca
  • dc.date.accessioned 2017-10-11T13:44:12Z
  • dc.date.available 2017-10-11T13:44:12Z
  • dc.date.issued 2015
  • dc.description.abstract BACKGROUND: Machado-Joseph Disease (MJD), a form of dominantly inherited ataxia belonging to the group of polyQ expansion neurodegenerative disorders, occurs when a threshold value for the number of glutamines in Ataxin-3 (Atx3) polyglutamine region is exceeded. As a result of its modular multidomain architecture, Atx3 is known to engage in multiple macromolecular interactions, which might be unbalanced when the polyQ tract is expanded, culminating in the aggregation and formation of intracellular inclusions, a unifying fingerprint of this group of neurodegenerative disorders. Since aggregation is specific to certain brain regions, localization-dependent posttranslational modifications that differentially affect Atx3 might also contribute for MJD. METHODS: We combined in vitro and cellular approaches to address SUMOylation in the brain-predominant Atx3 isoform and assessed the impact of this posttranslational modification on Atx3 self-assembly and interaction with its native partner, p97. RESULTS: We demonstrate that Atx3 is SUMOylated at K356 both in vitro and in cells, which contributes for decreased formation of amyloid fibrils and for increased affinity towards p97. CONCLUSIONS AND GENERAL SIGNIFICANCE: These findings highlight the role of SUMOylation as a regulator of Atx3 function, with implications on Atx3 protein interaction network and self-assembly, with potential impact for further understanding the molecular mechanisms underlying MJD pathogenesis.
  • dc.description.sponsorship This work was funded by the Fundação para a Ciência e a Tecnologia (FCT, Portugal) through grants PTDC/BIA-PRO/100059/2008 and PTDC/SAU-NMC/110602/2009 (EU-FEDER funding through COMPETEFCOMP-01-0124-FEDER-009031 and FCOMP-01-0124-FEDER-015860, respectively), and by QREN — Quadro de Referência Estratégica Nacional through Programa Operacional Regional do Norte ON. 2 (Neurodegenerative Disorders — NORTE-01-0124-FEDER-000001). C.M., S.F., I.A.A. and B.A. acknowledge the financial support from FCT through fellowships SFRH/BD/47160/2008, SFRH/BPD/77009/2011, Ciência 2008 Programme, and SFRH/BPD/70783/2010, respectively.
  • dc.format.mimetype application/pdfca
  • dc.identifier.citation Almeida B, Abreu IA, Matos CA, Fraga JS, Fernandes S, Macedo MG, [et al]. SUMOylation of the brain-predominant Ataxin-3 isoform modulates its interaction with p97. Biochim Biophys Acta. 2015;1852(9):1950-9. DOI: 10.1016/j.bbadis.2015.06.010
  • dc.identifier.doi http://dx.doi.org/10.1016/j.bbadis.2015.06.010
  • dc.identifier.issn 0006-3002
  • dc.identifier.uri http://hdl.handle.net/10230/32929
  • dc.language.iso eng
  • dc.publisher Elsevierca
  • dc.relation.ispartof Biochimica et Biophysica Acta. 2015;1852(9):1950-9
  • dc.rights © Elsevier This is the published version of an article http://dx.doi.org/10.1016/j.bbadis.2015.06.010 that appeared in the journal Biochim Biophys Acta. It is published in an Open Archive under an Elsevier user license. Details of this licence are available here: http://www.elsevier.com/about/open-access/open-access-policies/oa-license-policy/elsevier-user-license
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://www.elsevier.com/about/open-access/open-access-policies/oa-license-policy/elsevier-user-license
  • dc.subject.keyword Polyglutamine
  • dc.subject.keyword Posttranslational modification
  • dc.subject.keyword Protein aggregation
  • dc.subject.keyword Amyloid
  • dc.subject.keyword Surface plasmon resonance
  • dc.title SUMOylation of the brain-predominant Ataxin-3 isoform modulates its interaction with p97ca
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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