title: Conformational and aggregation properties of the 1-93 fragment of apolipoprotein A-I.
abstract: 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.
authors.affiliation: Department of Experimental Medical Science, Lund University, BMC Floor C12, SE-221 84, Lund, Sweden.
authors.forename: Jitka
authors.initials: J
authors.lastname: Petrlova
authors.forename: Arnab
authors.initials: A
authors.lastname: Bhattacherjee
authors.forename: Wouter
authors.initials: W
authors.lastname: Boomsma
authors.forename: Stefan
authors.initials: S
authors.lastname: Wallin
authors.forename: Jens O
authors.initials: JO
authors.lastname: Lagerstedt
authors.forename: Anders
authors.initials: A
authors.lastname: Irbäck
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism*; D016632:Apolipoprotein A-I / Q000737:chemistry* / Q000378:metabolism*; D002942:Circular Dichroism; D064267:Intrinsically Disordered Proteins / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D017433:Protein Structure, Secondary
chemical_list: D000682:Amyloid; D016632:Apolipoprotein A-I; D064267:Intrinsically Disordered Proteins
keywords: amyloidogenic mutations; disordered protein; fibril formation; molecular simulation; secondary-structure probability