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dc.contributor.authorSvanström, Andreas
dc.date.accessioned2016-03-23T12:23:31Z
dc.date.available2016-03-23T12:23:31Z
dc.date.issued2016-03-23
dc.identifier.isbn978-91-628-9748-2 (PDF)
dc.identifier.isbn978-91-628-9749-9 (Print)
dc.identifier.urihttp://hdl.handle.net/2077/41921
dc.description.abstractThe oligomeric chaperone CCT is a large ATP-dependent chaperonin that consists of two rings placed back-to-back with eight different paralogous subunits with a size of ~ 55 kDa that sit in each of the two rings. The function of CCT is mainly to fold the abundant proteins actin and tubulin, components of the cytoskeleton. However, several studies have shown that CCT has a wide diversity of low-abundant substrates. In addition, CCT and monomeric subunits of CCT have been shown to influence cytoskeletal organization and processes that the cytoskeleton mediates. The aim of this thesis was to study the role of CCT beyond the folding of proteins. We have overexpressed the subunits of CCT as monomers and demonstrated that monomeric CCTδ has an unknown function at the plasma membrane. The overexpression of monomeric CCTδ mainly induced lamellipodia retraction fibres and the function of monomeric CCTδ at the plasma membrane was shown to be dependent on a wild-type ATP-binding site and a wild-type apical domain of CCTδ. By reducing the levels of individual subunits of CCT, we report in a second study a function of CCTε to regulate the activity of the transcription factor SRF, which controls the transcription of cytoskeletal genes such as actin, via the transcription activator MRTF-A. Cells depleted of CCTε have an increased SRF-mediated transcription in an SRF-luciferase gene reporter system. Monomeric CCTε was shown to interact directly with MRTF-A and the interaction site was identified as the apical domain of CCTε and the cterminal half of MRTF-A. Consistent with an increased SRF-transcription upon the reduction of CCTε levels, the overexpression of monomeric CCTε delayed the translocation of MRTFA to the nucleus in serum-stimulated cells. In our final study, we addressed the possibility of CCT to affect the number of actin filaments via the interaction between CCT and the actin filament severing protein gelsolin. We showed that CCT binds to the activated severing conformation of gelsolin and that CCT inhibits activated gelsolin to sever actin filaments. Taken together, we present several studies that independently identify the CCT oligomer, or its individual subunits, to affect processes related to the cytoskeleton. Thus, there is a close interplay between CCT and the cytoskeleton that extends beyond the dependency of actin and tubulin to be folded by CCT.sv
dc.language.isoengsv
dc.relation.haspartI. Spiess M. et al. Over-Expression Analysis of All Eight Subunits of the Molecular Chaperone CCT in Mammalian Cells Reveals a Novel Function for CCTdelta. J Mol Biol. 2015; 427(17): 2757-64. ::doi::10.1016/j.jmb.2015.06.007sv
dc.relation.haspartII. Elliott K.L. et al. A novel function of the monomeric CCTepsilon subunit connects the serum response factor pathway to chaperone-mediated actin folding. Mol Biol Cell. 2015; 26(15): 2801-9. ::doi::10.1091/mbc.E15-01-0048sv
dc.relation.haspartIII. Svanström A. and J. Grantham. The molecular chaperone CCT modulates the activity of the actin filament severing and capping protein gelsolin in vitro. Cell Stress Chaperones. 2015; 21(1): 55-62. ::doi::10.1007/s12192-015-0637-5sv
dc.subjectCCT oligomersv
dc.subjectActinsv
dc.subjectCCT deltasv
dc.subjectCCT epsilonsv
dc.subjectGelsolinsv
dc.subjectMRTF-Asv
dc.subjectCell morphologysv
dc.titleThe Extended Role of the Molecular Chaperone CCTsv
dc.typeTextswe
dc.type.svepDoctoral thesiseng
dc.gup.mailandreas.svanstroem@gmail.comsv
dc.type.degreeDoctor of Philosophysv
dc.gup.originUniversity of Gothenburg. Faculty of Sciencesv
dc.gup.departmentDepartment of Chemistry and Molecular Biology ; Institutionen för kemi och molekylärbiologisv
dc.gup.defenceplaceTorsdagen den 28:e april 2016, kl. 10.00, Hörsal Carl Kylberg, Medicinaregatan 7sv
dc.gup.defencedate2016-04-28
dc.gup.dissdb-fakultetMNF


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