title: SUMOylation of the brain-predominant Ataxin-3 isoform modulates its interaction with p97.
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
  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.
authors.affiliation: IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, 4150-180 Porto, Portugal; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal.
authors.forename: Bruno
authors.initials: B
authors.lastname: Almeida
authors.affiliation: IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, 4150-180 Porto, Portugal; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal.
authors.forename: Isabel A
authors.initials: IA
authors.lastname: Abreu
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; Department of Life Sciences, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Matos
authors.affiliation: IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, 4150-180 Porto, Portugal; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal.
authors.forename: Joana S
authors.initials: JS
authors.lastname: Fraga
authors.affiliation: IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, 4150-180 Porto, Portugal; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal.
authors.forename: Sara
authors.initials: S
authors.lastname: Fernandes
authors.affiliation: IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, 4150-180 Porto, Portugal; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Macedo
authors.affiliation: Bioanalysis Group, Neurosciences Research Program, Hospital del Mar Medical Research Institute (IMIM)-Parque de Salud Mar, 08003 Barcelona, Spain; Department of Experimental and Health Sciences, Pompeu Fabra University, 08003 Barcelona, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gutiérrez-Gallego
authors.affiliation: IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, 4150-180 Porto, Portugal; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal.
authors.forename: Pedro José Barbosa
authors.initials: PJ
authors.lastname: Pereira
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; Department of Life Sciences, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Ana Luísa
authors.initials: AL
authors.lastname: Carvalho
authors.affiliation: IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, 4150-180 Porto, Portugal; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal. Electronic address: sribeiro@ibmc.up.pt.
authors.forename: Sandra
authors.initials: S
authors.lastname: Macedo-Ribeiro
keywords: Amyloid; Polyglutamine; Posttranslational modification; Protein aggregation; Surface plasmon resonance