Anionic phospholipid interactions of the prion protein N terminus are minimally perturbing and not driven solely by the octapeptide repeat domain

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dc.contributor.authorBoland, MPen_AU
dc.contributor.authorHatty, CRen_AU
dc.contributor.authorSeparovic, Fen_AU
dc.contributor.authorHill, AFen_AU
dc.contributor.authorTew, DJen_AU
dc.contributor.authorBarnham, KJen_AU
dc.contributor.authorHaigh, CLen_AU
dc.contributor.authorJames, Men_AU
dc.contributor.authorMasters, CLen_AU
dc.contributor.authorCollins, SJen_AU
dc.date.accessioned2010-10-25T23:27:29Zen_AU
dc.date.available2010-10-25T23:27:29Zen_AU
dc.date.issued2010-10-15en_AU
dc.date.statistics2010-10-15en_AU
dc.description.abstractAlthough the N terminus of the prion protein (PrPC) has been shown to directly associate with lipid membranes, the precise determinants, biophysical basis, and functional implications of such binding, particularly in relation to endogenously occurring fragments, are unresolved. To better understand these issues, we studied a range of synthetic peptides: specifically those equating to the N1 (residues 23–110) and N2 (23–89) fragments derived from constitutive processing of PrPC and including those representing arbitrarily defined component domains of the N terminus of mouse prion protein. Utilizing more physiologically relevant large unilamellar vesicles, fluorescence studies at synaptosomal pH (7.4) showed absent binding of all peptides to lipids containing the zwitterionic headgroup phosphatidylcholine and mixtures containing the anionic headgroups phosphatidylglycerol or phosphatidylserine. At pH 5, typical of early endosomes, quartz crystal microbalance with dissipation showed the highest affinity binding occurred with N1 and N2, selective for anionic lipid species. Of particular note, the absence of binding by individual peptides representing component domains underscored the importance of the combination of the octapeptide repeat and the N-terminal polybasic regions for effective membrane interaction. In addition, using quartz crystal microbalance with dissipation and solid-state NMR, we characterized for the first time that both N1 and N2 deeply insert into the lipid bilayer with minimal disruption. Potential functional implications related to cellular stress responses are discussed. © 2010, American Society for Biochemistry and Molecular Biologyen_AU
dc.identifier.citationBoland, M. P., Hatty, C. R., Separovic, F., Hill, A. F., Tew, D. J., Barnham, K. J., Haigh, C. L., James, M., Masters, C. L., & Collins, S. J. (2010). Anionic phospholipid interactions of the prion protein N terminus are minimally perturbing and not driven solely by the octapeptide repeat domain. Journal of Biological Chemistry, 285(42), 32282-32292. doi:10.1074/jbc.M110.123398en_AU
dc.identifier.govdoc2944en_AU
dc.identifier.issn0021-9258en_AU
dc.identifier.issue42en_AU
dc.identifier.journaltitleJournal of Biological Chemistryen_AU
dc.identifier.pagination32282-32292en_AU
dc.identifier.urihttp://dx.doi.org/10.1074/jbc.M110.123398en_AU
dc.identifier.urihttp://apo.ansto.gov.au/dspace/handle/10238/2764en_AU
dc.identifier.volume285en_AU
dc.language.isoenen_AU
dc.publisherAmerican Society for Biochemistry and Molecular Biologyen_AU
dc.subjectMembranesen_AU
dc.subjectLipidsen_AU
dc.subjectNuclear magnetic resonanceen_AU
dc.subjectSolid state physicsen_AU
dc.subjectMicrobalancesen_AU
dc.subjectPeptidesen_AU
dc.titleAnionic phospholipid interactions of the prion protein N terminus are minimally perturbing and not driven solely by the octapeptide repeat domainen_AU
dc.typeJournal Articleen_AU
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