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dc.contributor.authorPakdaman, Yasaman
dc.contributor.authorSanchez Guixe, Monica
dc.contributor.authorKleppe, Rune
dc.contributor.authorErdal, Sigrid
dc.contributor.authorBustad, Helene J.
dc.contributor.authorBjørkhaug, Lise
dc.contributor.authorHaugarvoll, Kristoffer
dc.contributor.authorTzoulis, Charalampos
dc.contributor.authorHeimdal, Ketil Riddervold
dc.contributor.authorKnappskog, Per
dc.contributor.authorJohansson, Stefan
dc.contributor.authorAukrust, Ingvild
dc.date.accessioned2019-03-11T08:48:43Z
dc.date.available2019-03-11T08:48:43Z
dc.date.created2017-07-04T07:54:32Z
dc.date.issued2017
dc.identifier.citationPakdaman, Y., Sanchez-Guixé, M., Kleppe, R., Erdal, S., Bustad, Helene J., Bjørkhaug, L., . . . Aukrust, I. (2017). In vitro characterization of six STUB1 variants in spinocerebellar ataxia 16 reveals altered structural properties for the encoded CHIP proteins. Bioscience Reports, 37(2).nb_NO
dc.identifier.issn0144-8463
dc.identifier.urihttp://hdl.handle.net/11250/2589493
dc.description.abstractSpinocerebellar ataxia, autosomal recessive 16 (SCAR16) is caused by biallelic mutations in the STIP1 homology and U-box containing protein 1 (STUB1) gene encoding the ubiquitin E3 ligase and dimeric co-chaperone C-terminus of Hsc70-interacting protein (CHIP). It has been proposed that the disease mechanism is related to CHIP’s impaired E3 ubiquitin ligase properties and/or interaction with its chaperones. However, there is limited knowledge on how these mutations affect the stability, folding, and protein structure of CHIP itself. To gain further insight, six previously reported pathogenic STUB1 variants (E28K, N65S, K145Q, M211I, S236T, and T246M) were expressed as recombinant proteins and studied using limited proteolysis, size-exclusion chromatography (SEC), and circular dichroism (CD). Our results reveal that N65S shows increased CHIP dimerization, higher levels of α-helical content, and decreased degradation rate compared with wild-type (WT) CHIP. By contrast, T246M demonstrates a strong tendency for aggregation, a more flexible protein structure, decreased levels of α-helical structures, and increased degradation rate compared with WT CHIP. E28K, K145Q, M211I, and S236T also show defects on structural properties compared with WT CHIP, although less profound than what observed for N65S and T246M. In conclusion, our results illustrate that some STUB1 mutations known to cause recessive SCAR16 have a profound impact on the protein structure, stability, and ability of CHIP to dimerize in vitro. These results add to the growing understanding on the mechanisms behind the disorder.nb_NO
dc.language.isoengnb_NO
dc.publisherKluwer Academic/Plenum Publishersnb_NO
dc.rightsNavngivelse 4.0 Internasjonal*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/deed.no*
dc.subjectCHIPnb_NO
dc.subjectco-chaperonenb_NO
dc.subjectprotein aggregationnb_NO
dc.subjectprotein misfoldingnb_NO
dc.subjectubiquitin ligasesnb_NO
dc.titleIn vitro characterization of six STUB1 variants in spinocerebellar ataxia 16 reveals altered structural properties for the encoded CHIP proteinsnb_NO
dc.typeJournal articlenb_NO
dc.typePeer reviewednb_NO
dc.description.versionpublishedVersionnb_NO
dc.rights.holder© 2017 The Author(s).nb_NO
dc.subject.nsiVDP::Medisinske Fag: 700nb_NO
dc.source.pagenumber1-12nb_NO
dc.source.volume37nb_NO
dc.source.journalBioscience Reportsnb_NO
dc.source.issue2nb_NO
dc.identifier.doi10.1042/BSR20170251
dc.identifier.cristin1480625
cristin.unitcode203,2,10,0
cristin.unitnameInstitutt for bio- og kjemiingeniørfag - Bergen
cristin.ispublishedtrue
cristin.fulltextoriginal
cristin.qualitycode1


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