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Conformational and aggregation properties of the 1-93 fragment of apolipoprotein A-I

Petrlova, Jitka LU ; Bhattacherjee, Arnab LU ; Boomsma, Wouter LU ; Wallin, Stefan LU ; Lagerstedt, Jens O LU and Irbäck, Anders LU (2014) In Protein Science 23(11). p.71-1559
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... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
keywords
Amyloid, Apolipoprotein A-I, Circular Dichroism, Intrinsically Disordered Proteins, Molecular Dynamics Simulation, Protein Structure, Secondary
in
Protein Science
volume
23
issue
11
pages
13 pages
publisher
The Protein Society
external identifiers
  • Scopus:84928950006
ISSN
1469-896X
DOI
10.1002/pro.2534
language
English
LU publication?
yes
id
4038a8fb-13d3-4b22-b70b-743cb6e1a95f
date added to LUP
2016-08-16 18:03:47
date last changed
2016-10-13 05:12:23
@misc{4038a8fb-13d3-4b22-b70b-743cb6e1a95f,
  abstract     = {<p>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.</p>},
  author       = {Petrlova, Jitka and Bhattacherjee, Arnab and Boomsma, Wouter and Wallin, Stefan and Lagerstedt, Jens O and Irbäck, Anders},
  issn         = {1469-896X},
  keyword      = {Amyloid,Apolipoprotein A-I,Circular Dichroism,Intrinsically Disordered Proteins,Molecular Dynamics Simulation,Protein Structure, Secondary},
  language     = {eng},
  number       = {11},
  pages        = {71--1559},
  publisher    = {ARRAY(0xa011360)},
  series       = {Protein Science},
  title        = {Conformational and aggregation properties of the 1-93 fragment of apolipoprotein A-I},
  url          = {http://dx.doi.org/10.1002/pro.2534},
  volume       = {23},
  year         = {2014},
}