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dc.contributor.authorWoodroof, Helen I.
dc.contributor.authorPogson, Joe H.
dc.contributor.authorBegley, Mike
dc.contributor.authorCantley, Lewis C.
dc.contributor.authorDeak, Maria
dc.contributor.authorCampbell, David G.
dc.contributor.authorvan Aalten, Daan M. F.
dc.contributor.authorWhitworth, Alexander J.
dc.contributor.authorAlessi, Dario R.
dc.contributor.authorMuqit, Miratul M. K.
dc.date.accessioned2013-03-08T21:18:53Z
dc.date.issued2011
dc.identifier.citationWoodroof, Helen I., Joe H. Pogson, Mike Begley, Lewis C. Cantley, Maria Deak, David G. Campbell, Daan M. F. van Aalten, Alexander J. Whitworth, Dario R. Alessi, and Miratul M. K. Muqit. 2011. Discovery of catalytically active orthologues of the Parkinson's disease kinase PINK1: Analysis of substrate specificity and impact of mutations. Open Biology 1(3): 110012.en_US
dc.identifier.issn2046-2441en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:10382850
dc.description.abstractMissense mutations of the phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) gene cause autosomal-recessive Parkinson's disease. To date, little is known about the intrinsic catalytic properties of PINK1 since the human enzyme displays such low kinase activity in vitro. We have discovered that, in contrast to mammalian PINK1, insect orthologues of PINK1 we have investigated—namely Drosophila melanogaster (dPINK1), Tribolium castaneum (TcPINK1) and Pediculus humanus corporis (PhcPINK1)—are active as judged by their ability to phosphorylate the generic substrate myelin basic protein. We have exploited the most active orthologue, TcPINK1, to assess its substrate specificity and elaborated a peptide substrate (PINKtide, KKWIpYRRSPRRR) that can be employed to quantify PINK1 kinase activity. Analysis of PINKtide variants reveal that PINK1 phosphorylates serine or threonine, but not tyrosine, and we show that PINK1 exhibits a preference for a proline at the +1 position relative to the phosphorylation site. We have also, for the first time, been able to investigate the effect of Parkinson's disease-associated PINK1 missense mutations, and found that nearly all those located within the kinase domain, as well as the C-terminal non-catalytic region, markedly suppress kinase activity. This emphasizes the crucial importance of PINK1 kinase activity in preventing the development of Parkinson's disease. Our findings will aid future studies aimed at understanding how the activity of PINK1 is regulated and the identification of physiological substrates.en_US
dc.language.isoen_USen_US
dc.publisherThe Royal Societyen_US
dc.relation.isversionofdoi:10.1098/rsob.110012en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3352081/pdf/en_US
dash.licenseLAA
dc.subjectbiochemistryen_US
dc.subjectParkinson’s diseaseen_US
dc.subjectkinaseen_US
dc.titleDiscovery of Catalytically Active Orthologues of the Parkinson's Disease Kinase PINK1: Analysis of Substrate Specificity and Impact of Mutationsen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalOpen Biologyen_US
dash.depositing.authorCantley, Lewis C.
dc.date.available2013-03-08T21:18:53Z
dc.identifier.doi10.1098/rsob.110012*
dash.contributor.affiliatedCantley, Lewis C.


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