Conformational and aggregation properties of the 1-93 fragment of apolipoprotein A-I.
Several disease-linked mutations of apolipoprotein A-I, the major protein in high-density lipoprotein (HDL), are known to be amyloidogenic, and the fibrils often contain N-terminal fragments of the protein. Here, we present a combined computational and experimental study of the fibril-associated disordered 1-93 fragment of this protein, in wild-type and mutated (G26R, S36A, K40L, W50R) forms. In atomic-level Monte Carlo simulations of the free monomer, validated by circular dichroism spectroscopy, we observe changes in the position-dependent β-strand probability induced by mutations. We find that these conformational shifts match well with the effects of these mutations in thioflavin T fluorescence and transmission electron microscopy experiments. Together, our results point to molecular mechanisms that may have a key role in disease-linked aggregation of apolipoprotein A-I.
['Petrlova|Jitka|J|', 'Bhattacherjee|Arnab|A|', 'Boomsma|Wouter|W|', 'Wallin|Stefan|S|', 'Lagerstedt|Jens O|JO|', 'Irbäck|Anders|A|']
D000682:Amyloid D016632:Apolipoprotein A-I D002942:Circular Dichroism D064267:Intrinsically Disordered Proteins D056004:Molecular Dynamics Simulation D017433:Protein Structure, Secondary
amyloidogenic mutations disordered protein fibril formation molecular simulation secondary-structure probability