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dc.contributor.authorBongiovanni, Marie
dc.contributor.authorAprile, Francesco
dc.contributor.authorSormanni, Pietro
dc.contributor.authorVendruscolo, Michele
dc.date.accessioned2018-11-13T00:30:08Z
dc.date.available2018-11-13T00:30:08Z
dc.date.issued2018-05-12
dc.identifier.issn1661-6596
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/284941
dc.description.abstractMolecular chaperones are key components of the protein homeostasis system against protein misfolding and aggregation. It has been recently shown that these molecules can be rationally modified to have an enhanced activity against specific amyloidogenic substrates. The resulting molecular chaperone variants can be effective inhibitors of protein aggregation in vitro, thus suggesting that they may provide novel opportunities in biomedical and biotechnological applications. Before such opportunities can be exploited, however, their effects on cell viability should be better characterised. Here, we employ a rational design method to specifically enhance the activity of the 70-kDa heat shock protein (Hsp70) against the aggregation of the human islet amyloid polypeptide (hIAPP, also known as amylin). We then show that the Hsp70 variant that we designed (grafted heat shock protein 70 kDa-human islet amyloid polypeptide, GHsp70-hIAPP) is significantly more effective than the wild type in recovering the viability of cultured pancreatic islet β-cells RIN-m5F upon hIAPP aggregation. These results indicate that a full recovery of the toxic effects of hIAPP aggregates on cultured pancreatic cells can be achieved by increasing the specificity and activity of Hsp70 towards hIAPP, thus providing evidence that the strategy presented here provides a possible route for rationally tailoring molecular chaperones for enhancing their effects in a target-dependent manner.
dc.description.sponsorshipAlzheimer's Society UK
dc.format.mediumElectronic
dc.languageeng
dc.publisherMDPI AG
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectCells, Cultured
dc.subjectCell Line
dc.subjectHumans
dc.subjectCell Survival
dc.subjectHSP70 Heat-Shock Proteins
dc.subjectInsulin-Secreting Cells
dc.subjectGenetic Variation
dc.subjectAmyloid beta-Peptides
dc.subjectIslet Amyloid Polypeptide
dc.subjectProtein Aggregates
dc.subjectProtein Aggregation, Pathological
dc.titleA Rationally Designed Hsp70 Variant Rescues the Aggregation-Associated Toxicity of Human IAPP in Cultured Pancreatic Islet β-Cells.
dc.typeArticle
prism.issueIdentifier5
prism.publicationDate2018
prism.publicationNameInt J Mol Sci
prism.volume19
dc.identifier.doi10.17863/CAM.32313
dcterms.dateAccepted2018-05-08
rioxxterms.versionofrecord10.3390/ijms19051443
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-05-12
dc.contributor.orcidAprile, Francesco [0000-0002-5040-4420]
dc.contributor.orcidSormanni, Pietro [0000-0002-6228-2221]
dc.contributor.orcidVendruscolo, Michele [0000-0002-3616-1610]
dc.identifier.eissn1422-0067
rioxxterms.typeJournal Article/Review
cam.issuedOnline2018-05-12


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International