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Enhancement of the anti-aggregation activity of a molecular chaperone using a rationally designed post-translational modification

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dc.contributor.authorLindstedt, Philip R.
dc.contributor.authorAprile, Francesco A.
dc.contributor.authorMatos, Maria J.
dc.contributor.authorPerni, Michele
dc.contributor.authorBertoldo, Jean B.
dc.contributor.authorBernardim, Barbara
dc.contributor.authorPeter, Quentin
dc.contributor.authorJiménez-Osés, Gonzalo
dc.contributor.authorKnowles, Tuomas P. J.
dc.contributor.authorDobson, Christopher M.
dc.contributor.authorCorzana, Francisco
dc.contributor.authorVendruscolo, Michele
dc.contributor.authorBernardes, Gonçalo J. L.
dc.date.accessioned2021-10-15T14:07:26Z
dc.date.available2021-10-15T14:07:26Z
dc.date.issued2019
dc.descriptionCopyright © 2019 American Chemical Societypt_PT
dc.description.abstractProtein behavior is closely regulated by a plethora of post-translational modifications (PTMs). It is therefore desirable to develop approaches to design rational PTMs to modulate specific protein functions. Here, we report one such method, and we illustrate its successful implementation by potentiating the anti-aggregation activity of a molecular chaperone. Molecular chaperones are a multifaceted class of proteins essential to protein homeostasis, and one of their major functions is to combat protein misfolding and aggregation, a phenomenon linked to a number of human disorders. In this work, we conjugated a small-molecule inhibitor of the aggregation of α-synuclein, a process associated with Parkinson's disease (PD), to a specific cysteine residue on human Hsp70, a molecular chaperone with five free cysteines. We show that this regioselective conjugation augments in vitro the anti-aggregation activity of Hsp70 in a synergistic manner. This Hsp70 variant also displays in vivo an enhanced suppression of α-synuclein aggregation and its associated toxicity in a Caenorhabditis elegans model of PD.pt_PT
dc.description.sponsorshipWe thank Alzheimer’s Society UK (Senior Research Fellowship to F.A.A., Grant No. 317, AS-SF-16-003), Xunta de Galicia (postdoctoral Fellowship to M.J.M., ED481B 2014/086-0), Ministerio de Ciencia, Innovación y Universidades (Project RTI2018-099592-B-C21 to F.C.), FCT Portugal (FCT Investigator to G.J.L.B., iFCT IF/00624/2015), CNPq Brazil (postdoctoral Fellowship 200456/2015-6 to J.B.B.), Royal Society (NIF\R1\180120 to B.B.) and FAPESP (BEPE 2017/13168-8 to B.B.) for funding. G.J.L.B. is a Royal Society URF (URF\R\180019).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationACS Cent Sci. 2019 Aug 28;5(8):1417-1424pt_PT
dc.identifier.doi10.1021/acscentsci.9b00467pt_PT
dc.identifier.eissn2374-7951
dc.identifier.urihttp://hdl.handle.net/10451/49910
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherACS Publicationspt_PT
dc.relationIF/00624/2015pt_PT
dc.relation.publisherversionhttps://pubs.acs.org/loi/acsciipt_PT
dc.titleEnhancement of the anti-aggregation activity of a molecular chaperone using a rationally designed post-translational modificationpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage1424pt_PT
oaire.citation.issue8pt_PT
oaire.citation.startPage1417pt_PT
oaire.citation.titleACS Central Sciencept_PT
oaire.citation.volume5pt_PT
person.familyNameBernardes
person.givenNameGonçalo
person.identifier.orcid0000-0001-6594-8917
person.identifier.scopus-author-id14046757500
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublicationd1a48067-77b1-4413-b1c7-602fb18c62c0
relation.isAuthorOfPublication.latestForDiscoveryd1a48067-77b1-4413-b1c7-602fb18c62c0

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