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The cellular modifier MOAG-4/SERF drives amyloid formation through charge complementation.

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cam.issuedOnline2021-10-07
dc.contributor.authorPras, Anita
dc.contributor.authorHouben, Bert
dc.contributor.authorAprile, Francesco A
dc.contributor.authorSeinstra, Renée
dc.contributor.authorGallardo, Rodrigo
dc.contributor.authorJanssen, Leen
dc.contributor.authorHogewerf, Wytse
dc.contributor.authorGallrein, Christian
dc.contributor.authorDe Vleeschouwer, Matthias
dc.contributor.authorMata-Cabana, Alejandro
dc.contributor.authorKoopman, Mandy
dc.contributor.authorStroo, Esther
dc.contributor.authorde Vries, Minke
dc.contributor.authorLouise Edwards, Samantha
dc.contributor.authorKirstein, Janine
dc.contributor.authorVendruscolo, Michele
dc.contributor.authorFalsone, Salvatore Fabio
dc.contributor.authorRousseau, Frederic
dc.contributor.authorSchymkowitz, Joost
dc.contributor.authorNollen, Ellen AA
dc.contributor.orcidPras, Anita [0000-0003-2752-152X]
dc.contributor.orcidHouben, Bert [0000-0002-6750-011X]
dc.contributor.orcidAprile, Francesco A [0000-0002-5040-4420]
dc.contributor.orcidSeinstra, Renée [0000-0001-5083-399X]
dc.contributor.orcidJanssen, Leen [0000-0002-1973-304X]
dc.contributor.orcidGallrein, Christian [0000-0002-7623-2778]
dc.contributor.orcidMata-Cabana, Alejandro [0000-0002-0179-2746]
dc.contributor.orcidKoopman, Mandy [0000-0003-1429-2078]
dc.contributor.orcidLouise Edwards, Samantha [0000-0002-7722-5959]
dc.contributor.orcidKirstein, Janine [0000-0003-4990-2497]
dc.contributor.orcidVendruscolo, Michele [0000-0002-3616-1610]
dc.contributor.orcidFalsone, Salvatore Fabio [0000-0002-3724-5824]
dc.contributor.orcidRousseau, Frederic [0000-0002-9189-7399]
dc.contributor.orcidSchymkowitz, Joost [0000-0003-2020-0168]
dc.contributor.orcidNollen, Ellen AA [0000-0003-3740-6373]
dc.date.accessioned2021-11-25T17:28:27Z
dc.date.available2021-11-25T17:28:27Z
dc.date.issued2021-11-02
dc.description.abstractWhile aggregation-prone proteins are known to accelerate aging and cause age-related diseases, the cellular mechanisms that drive their cytotoxicity remain unresolved. The orthologous proteins MOAG-4, SERF1A, and SERF2 have recently been identified as cellular modifiers of such proteotoxicity. Using a peptide array screening approach on human amyloidogenic proteins, we found that SERF2 interacted with protein segments enriched in negatively charged and hydrophobic, aromatic amino acids. The absence of such segments, or the neutralization of the positive charge in SERF2, prevented these interactions and abolished the amyloid-promoting activity of SERF2. In protein aggregation models in the nematode worm Caenorhabditis elegans, protein aggregation and toxicity were suppressed by mutating the endogenous locus of MOAG-4 to neutralize charge. Our data indicate that MOAG-4 and SERF2 drive protein aggregation and toxicity by interactions with negatively charged segments in aggregation-prone proteins. Such charge interactions might accelerate primary nucleation of amyloid by initiating structural changes and by decreasing colloidal stability. Our study points at charge interactions between cellular modifiers and amyloidogenic proteins as potential targets for interventions to reduce age-related protein toxicity.
dc.format.mediumPrint-Electronic
dc.identifier.doi10.17863/CAM.78617
dc.identifier.eissn1460-2075
dc.identifier.issn0261-4189
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/331170
dc.languageeng
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.publisher.urlhttp://dx.doi.org/10.15252/embj.2020107568
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectMOAG-4
dc.subjectSERF
dc.subjectamyloid
dc.subjectprotein aggregation
dc.subjectprotein quality control
dc.subjectAmino Acid Sequence
dc.subjectAmyloid
dc.subjectAmyloidogenic Proteins
dc.subjectAnimals
dc.subjectBinding Sites
dc.subjectCaenorhabditis elegans
dc.subjectCaenorhabditis elegans Proteins
dc.subjectGene Expression Regulation
dc.subjectHEK293 Cells
dc.subjectHumans
dc.subjectHydrophobic and Hydrophilic Interactions
dc.subjectIntracellular Signaling Peptides and Proteins
dc.subjectNerve Tissue Proteins
dc.subjectPeptides
dc.subjectProtein Aggregates
dc.subjectProtein Array Analysis
dc.subjectProtein Binding
dc.subjectSignal Transduction
dc.subjectStatic Electricity
dc.subjectalpha-Synuclein
dc.titleThe cellular modifier MOAG-4/SERF drives amyloid formation through charge complementation.
dc.typeArticle
dcterms.dateAccepted2021-09-01
prism.publicationDate2021
prism.publicationNameEMBO J
prism.startingPagee107568
rioxxterms.licenseref.startdate2021-10-07
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.15252/embj.2020107568

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