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dc.contributor.authorRijal, Ramesh
dc.contributor.authorArhzaouy, Khalid
dc.contributor.authorStrucksberg, Karl-Heinz
dc.contributor.authorCross, Megan
dc.contributor.authorHofmann, Andreas
dc.contributor.authorSchroeder, Rolf
dc.contributor.authorClemen, Christoph S
dc.contributor.authorEichinger, Ludwig
dc.date.accessioned2017-12-14T01:21:54Z
dc.date.available2017-12-14T01:21:54Z
dc.date.issued2016
dc.identifier.issn0171-9335
dc.identifier.doi10.1016/j.ejcb.2016.03.004
dc.identifier.urihttp://hdl.handle.net/10072/99957
dc.description.abstractp97 (VCP) is a homo-hexameric triple-A ATPase that exerts a plethora of cellular processes. Heterozygous missense mutations of p97 cause at least five human neurodegenerative disorders. However, the specific molecular consequences of p97 mutations are hitherto widely unknown. Our in silico structural models of human and Dictyostelium p97 showed that the disease-causing human R93C, R155H, and R155C as well as Dictyostelium R154C, E219K, R154C/E219K p97 mutations constitute variations in surface-exposed locations. In-gel ATPase activity measurements of p97 monomers and hexamers revealed significant mutation- and species-specific differences. While all human p97 mutations led to an increase in ATPase activity, no changes could be detected for the Dictyostelium R154C mutant, which is orthologous to human R155C. The E219K mutation led to an almost complete loss of activity, which was partially recuperated in the R154C/E219K double-mutant indicating p97 inter-domain communication. By means of co-immunoprecipitation experiments we identified an UBX-domain containing Dictyostelium protein as a novel p97 interaction partner. We categorized all UBX-domain containing Dictyostelium proteins and named the interaction partner UBXD9. Pull-down assays and surface plasmon resonance analyses of Dictyostelium UBXD9 or the human orthologue TUG/ASPL/UBXD9 demonstrated direct interactions with p97 as well as species-, mutation- and ATP-dependent differences in the binding affinities. Sucrose density gradient assays revealed that both human and Dictyostelium UBXD9 proteins very efficiently disassembled wild-type, but to a lesser extent mutant p97 hexamers into monomers. Our results are consistent with a scenario in which p97 point mutations lead to differences in enzymatic activities and molecular interactions, which in the long-term result in a late-onset and progressive multisystem disease.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherElsevier
dc.relation.ispartofpagefrom195
dc.relation.ispartofpageto207
dc.relation.ispartofissue6-7
dc.relation.ispartofjournalEuropean Journal of Cell Biology
dc.relation.ispartofvolume95
dc.subject.fieldofresearchBiochemistry and cell biology
dc.subject.fieldofresearchBiochemistry and cell biology not elsewhere classified
dc.subject.fieldofresearchPlant biology
dc.subject.fieldofresearchcode3101
dc.subject.fieldofresearchcode310199
dc.subject.fieldofresearchcode3108
dc.titleMutant p97 exhibits species-specific changes of its ATPase activity and compromises the UBXD9-mediated monomerisation of p97 hexamers
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
dcterms.licensehttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© 2016 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.
gro.hasfulltextFull Text
gro.griffith.authorHofmann, Andreas
gro.griffith.authorCross, Megan O.


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