Native disulphide-linked dimers facilitate amyloid fibril formation by bovine milk αS2-casein

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dc.contributor.authorThorn, DCen_AU
dc.contributor.authorBahraminejad, Een_AU
dc.contributor.authorGrosas, ABen_AU
dc.contributor.authorKouldelka, Ten_AU
dc.contributor.authorHoffmann, Pen_AU
dc.contributor.authorMata, JPen_AU
dc.contributor.authorDevlin, GLen_AU
dc.contributor.authorSunde, Men_AU
dc.contributor.authorEcroyd, Hen_AU
dc.contributor.authorHolt, Cen_AU
dc.contributor.authorCarver, JAen_AU
dc.date.accessioned2023-11-08T04:46:55Zen_AU
dc.date.available2023-11-08T04:46:55Zen_AU
dc.date.issued2021-03en_AU
dc.date.statistics2023-11-07en_AU
dc.descriptionDedicated to the memory of Prof. Sir Chris Dobson FRS, who encouraged, supported, inspired, and mentored many of this manuscript's authors and provided significant intellectual and critical input into our investigations of protein aggregation, including of caseins.en_AU
dc.description.abstractBovine milk αS2-casein, an intrinsically disordered protein, readily forms amyloid fibrils in vitro and is implicated in the formation of amyloid fibril deposits in mammary tissue. Its two cysteine residues participate in the formation of either intra- or intermolecular disulphide bonds, generating monomer and dimer species. X-ray solution scattering measurements indicated that both forms of the protein adopt large, spherical oligomers at 20 °C. Upon incubation at 37 °C, the disulphide-linked dimer showed a significantly greater propensity to form amyloid fibrils than its monomeric counterpart. Thioflavin T fluorescence, circular dichroism and infrared spectra were consistent with one or both of the dimer isomers (in a parallel or antiparallel arrangement) being predisposed toward an ordered, amyloid-like structure. Limited proteolysis experiments indicated that the region from Ala81 to Lys113 is incorporated into the fibril core, implying that this region, which is predicted by several algorithms to be amyloidogenic, initiates fibril formation of αS2-casein. The partial conservation of the cysteine motif and the frequent occurrence of disulphide-linked dimers in mammalian milks despite the associated risk of mammary amyloidosis, suggest that the dimeric conformation of αS2-casein is a functional, yet amyloidogenic, structure. © 2020 Elsevier B.Ven_AU
dc.description.sponsorshipThis work was supported by grants (to JAC) from Dairy Australia, the Australian Research Council and the National Health and Medical Research Council. HE was supported by a National Health and Medical Research Council Peter Doherty Fellowship and DCT was supported by a postgraduate research scholarship from Dairy Australia. We thank Lyn Waterhouse at Adelaide Microscopy for her assistance with TEM. We also thank Dr. Georgia Arentz from the Adelaide Proteomics Centre, University of Adelaide, for assistance with the collection of MS data. We gratefully acknowledge Dr. Robert Knott (Australian Centre for Neutron Scattering, ANSTO) for assistance with the collection of SAXS data, and the staff of Sydney Analytical core research facility at the University of Sydney for maintenance of X-ray diffraction equipment.en_AU
dc.identifier.articlenumber106530en_AU
dc.identifier.citationThorn, D. C., Bahraminejad, E., Grosas, A. B., Koudelka, T., Hoffmann, P., Mata, J. P., .Devlin, G. L., Sunde, M., Ecroyd, H., Holt, C., & Carver, J. A. (2021). Native disulphide-linked dimers facilitate amyloid fibril formation by bovine milk αS2-casein. Biophysical Chemistry, 270, 106530. doi:10.1016/j.bpc.2020.106530en_AU
dc.identifier.issn0301-4622en_AU
dc.identifier.journaltitleBiophysical Chemistryen_AU
dc.identifier.urihttps://apo.ansto.gov.au/handle/10238/15184en_AU
dc.identifier.volume270en_AU
dc.language.isoenen_AU
dc.publisherElsevieren_AU
dc.relation.urihttps://doi.org/10.1016/j.bpc.2020.106530en_AU
dc.subjectMilken_AU
dc.subjectCaseinen_AU
dc.subjectProteinsen_AU
dc.subjectDisulfidesen_AU
dc.subjectMonomersen_AU
dc.subjectDimersen_AU
dc.subjectCowsen_AU
dc.subjectX-ray diffractionen_AU
dc.titleNative disulphide-linked dimers facilitate amyloid fibril formation by bovine milk αS2-caseinen_AU
dc.typeJournal Articleen_AU
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