title: Apolipoprotein C-II Adopts Distinct Structures in Complex with Micellar and Submicellar Forms of the Amyloid-Inhibiting Lipid-Mimetic Dodecylphosphocholine.
abstract: The formation of amyloid deposits is a common feature of a broad range of diseases, including atherosclerosis, Alzheimer's disease, and Parkinson's disease. The basis and role of amyloid deposition in the pathogenesis of these diseases is still being defined, however an interesting feature of amyloidogenic proteins is that the majority of the pathologically associated proteins are involved in lipid homeostasis, be it in lipid transport, incorporation into membranes, or the regulation of lipid pathways. Thus, amyloid-forming proteins commonly bind lipids, and lipids are generally involved in the proper folding of these proteins. However, understanding of the basis for these lipid-related aspects of amyloidogenesis is lacking. Thus, we have used the apolipoprotein C-II amyloid model system in conjunction with x-ray and neutron scattering analyses to address this problem. Apolipoprotein C-II is a well-studied model system of systemic amyloid fibril formation, with a clear and well-defined pathway for fibril formation, where the effects of lipid interaction are characterized, particularly for the lipid mimetic dodecylphosphocholine. We show that the micellar state of an inhibitory lipid can have a very significant effect on protein conformation, with micelles stabilizing a particular α-helical structure, whereas submicellar lipids stabilize a very different dimeric, α-helical structure. These results indicate that lipids may have an important role in the development and progression of amyloid-related diseases.
authors.affiliation: Australian Synchrotron, Clayton, Victoria, Australia; The Florey Institute, The University of Melbourne, Parkville, Victoria, Australia; The MacDiarmid Institute of Advanced Materials and Nanotechnology, Wellington, New Zealand. Electronic address: tim.ryan@synchrotron.org.au.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Ryan
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Michael D W
authors.initials: MD
authors.lastname: Griffin
authors.affiliation: School of Chemical Science, The University of Auckland, Auckland, New Zealand; The MacDiarmid Institute of Advanced Materials and Nanotechnology, Wellington, New Zealand.
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: McGillivray
authors.affiliation: Australian Nuclear Science and Technology Organisation, New South Wales, Australia.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Knott
authors.affiliation: Australian Nuclear Science and Technology Organisation, New South Wales, Australia.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Wood
authors.affiliation: The Florey Institute, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.affiliation: Australian Synchrotron, Clayton, Victoria, Australia.
authors.forename: Nigel
authors.initials: N
authors.lastname: Kirby
authors.affiliation: The Florey Institute, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Cyril C
authors.initials: CC
authors.lastname: Curtain
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D053304:Apolipoprotein C-II / Q000737:chemistry* / Q000378:metabolism; D040761:Biomimetic Materials / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008055:Lipids / Q000737:chemistry*; D008823:Micelles; D008958:Models, Molecular; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D066329:Protein Aggregates / Q000187:drug effects; D011487:Protein Conformation; D055550:Protein Stability
chemical_list: D000682:Amyloid; D053304:Apolipoprotein C-II; D008055:Lipids; D008823:Micelles; D066329:Protein Aggregates; D010767:Phosphorylcholine; C028810:dodecylphosphocholine