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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 orcid (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
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
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
  • pmid:25131953
  • scopus:84928950006
  • wos:000344325900008
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
2024-01-04 10:55:10
@article{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}},
  keywords     = {{Amyloid; Apolipoprotein A-I; Circular Dichroism; Intrinsically Disordered Proteins; Molecular Dynamics Simulation; Protein Structure, Secondary}},
  language     = {{eng}},
  number       = {{11}},
  pages        = {{71--1559}},
  publisher    = {{The Protein Society}},
  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}},
  doi          = {{10.1002/pro.2534}},
  volume       = {{23}},
  year         = {{2014}},
}