Abstract
Apolipoproteins are a key component of lipid transport in the circulatory system and share a number of structural features that facilitate this role. When bound to lipoprotein particles, these proteins are relatively stable. However, in the absence of lipids they display conformational instability and a propensity to aggregate into amyloid fibrils. Apolipoprotein C-II (apoC-II) is a member of the apolipoprotein family that has been well characterised in terms of its misfolding and aggregation. In the absence of lipid, and at physiological ionic strength and pH, apoC-II readily forms amyloid fibrils with a twisted ribbon-like morphology that are amenable to a range of biophysical and structural analyses. Consistent with its lipid binding function, the misfolding and aggregation of apoC-II are substantially affected by the presence of lipid. Short-chain phospholipids at submicellar concentrations significantly accelerate amyloid formation by inducing a tetrameric form of apoC-II that can nucleate fibril aggregation. Conversely, phospholipid micelles and bilayers inhibit the formation of apoC-II ribbon-type fibrils, but induce slow formation of amyloid with a distinct straight fibril morphology. Our studies of the effects of lipid at each stage of amyloid formation, detailed in this chapter, have revealed complex behaviour dependent on the chemical nature of the lipid molecule, its association state, and the protein:lipid ratio.
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- Apo:
-
Apolipoprotein
- CD:
-
Circular dichroism
- CMC:
-
Critical micelle concentration
- DHPC:
-
1,2-dihexanoyl-sn-glycero-3 -phosphocholine
- DHPS:
-
1,2-dihexanoyl-sn-glycero-3-phospho-L-serine
- DMPC:
-
1,2-dimyristoyl-sn-glycero-3-phosphocholine
- DnPC:
-
1,2-diacyl-sn-glycero-3- phosphocholine where n = 3–9 carbon acyl chains
- DPC:
-
Dodecylphosphocholine
- FRET:
-
Fluorescence resonance energy transfer
- LysoMPC:
-
1-myristoyl-2-hydroxy-sn-glycero -3-phosphocholine
- NBD:
-
Nitrobenzoxadiazole
- SDS:
-
Sodium dodecyl sulphate
- STEM:
-
Scanning transmission electron microscopy
- TEM:
-
Transmission electron microscopy
- ThT:
-
Thioflavin T
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Acknowledgments
T.M.R. is the recipient of the Alzheimer’s Australia Dementia Research Foundation Fellowship. M.D.W.G is the recipient of the C.R. Roper Fellowship and an Australian Research Council Post Doctoral Fellowship (project number DP110103528). This work was supported by grants from the Australian Research Council and the National Health and Medical Research Council.
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Ryan, T.M., Mok, YF., Howlett, G.J., Griffin, M.D.W. (2015). The Role of Lipid in Misfolding and Amyloid Fibril Formation by Apolipoprotein C-II. In: Gursky, O. (eds) Lipids in Protein Misfolding. Advances in Experimental Medicine and Biology, vol 855. Springer, Cham. https://doi.org/10.1007/978-3-319-17344-3_7
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DOI: https://doi.org/10.1007/978-3-319-17344-3_7
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