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Mouse ApoM Displays an Unprecedented Seven-Stranded Lipocalin Fold: Folding Decoy or Alternative Native Fold?

Sevvana, Madhumati; Kassler, Kristin; Ahnström, Josefin LU ; Weiler, Sigrid; Dahlbäck, Björn LU ; Sticht, Heinrich and Muller, Yves A. (2010) In Journal of Molecular Biology 404(3). p.363-371
Abstract
Mouse apolipoprotein M (m-apoM) displays a 79% sequence identity to human apolipoprotein M (h-apoM). Both proteins are apolipoproteins associated with high-density lipoproteins, with similar anticipated biological functions. The structure of h-apoM has recently been determined by X-ray crystallography, which revealed that h-apoM displays, as expected, a lipocalin-like fold characterized by an eight-stranded 13 barrel that encloses an internal fatty-acid-binding site. Surprisingly, this is not true for m-apoM. After refolding from inclusion bodies, the crystal structure of m-apoM (reported here at 2.5 angstrom resolution) displays a novel yet unprecedented seven-stranded beta-barrel structure. The fold difference is not caused by a mere... (More)
Mouse apolipoprotein M (m-apoM) displays a 79% sequence identity to human apolipoprotein M (h-apoM). Both proteins are apolipoproteins associated with high-density lipoproteins, with similar anticipated biological functions. The structure of h-apoM has recently been determined by X-ray crystallography, which revealed that h-apoM displays, as expected, a lipocalin-like fold characterized by an eight-stranded 13 barrel that encloses an internal fatty-acid-binding site. Surprisingly, this is not true for m-apoM. After refolding from inclusion bodies, the crystal structure of m-apoM (reported here at 2.5 angstrom resolution) displays a novel yet unprecedented seven-stranded beta-barrel structure. The fold difference is not caused by a mere deletion of a single beta-strand; instead, beta-strands E and F are removed and replaced by a single beta-strand A' formed from residues from the N-terminus. Molecular dynamics simulations suggest that m-apoM is able to adopt both a seven-stranded barrel structure and an eight-stranded barrel structure in solution, and that both folds are comparably stable. Thermal unfolding simulations identify the position where beta-strand exchange occurs as the weak point of the beta-barrel. We wonder whether the switch in topology could have a biological function and could facilitate ligand release, since it goes hand in hand with a narrowing of the barrel diameter. Possibly also, the observed conformation represents an on-pathway or off-pathway folding intermediate of apoM. The difference in fold topology is quite remarkable, and the fold promiscuity observed for m-apoM might possibly provide a glimpse at potential cross-points during the evolution of beta-barrels. (c) 2010 Elsevier Ltd. All rights reserved. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
apolipoprotein, alternative conformations, misfolding, refolding, lipocalin
in
Journal of Molecular Biology
volume
404
issue
3
pages
363 - 371
publisher
Elsevier
external identifiers
  • wos:000285372700002
  • scopus:78349307798
ISSN
1089-8638
DOI
10.1016/j.jmb.2010.09.062
language
English
LU publication?
yes
id
80caf411-3364-460d-9ab2-21d0c8ca1f9d (old id 1772477)
date added to LUP
2011-02-02 20:55:24
date last changed
2018-05-29 11:04:30
@article{80caf411-3364-460d-9ab2-21d0c8ca1f9d,
  abstract     = {Mouse apolipoprotein M (m-apoM) displays a 79% sequence identity to human apolipoprotein M (h-apoM). Both proteins are apolipoproteins associated with high-density lipoproteins, with similar anticipated biological functions. The structure of h-apoM has recently been determined by X-ray crystallography, which revealed that h-apoM displays, as expected, a lipocalin-like fold characterized by an eight-stranded 13 barrel that encloses an internal fatty-acid-binding site. Surprisingly, this is not true for m-apoM. After refolding from inclusion bodies, the crystal structure of m-apoM (reported here at 2.5 angstrom resolution) displays a novel yet unprecedented seven-stranded beta-barrel structure. The fold difference is not caused by a mere deletion of a single beta-strand; instead, beta-strands E and F are removed and replaced by a single beta-strand A' formed from residues from the N-terminus. Molecular dynamics simulations suggest that m-apoM is able to adopt both a seven-stranded barrel structure and an eight-stranded barrel structure in solution, and that both folds are comparably stable. Thermal unfolding simulations identify the position where beta-strand exchange occurs as the weak point of the beta-barrel. We wonder whether the switch in topology could have a biological function and could facilitate ligand release, since it goes hand in hand with a narrowing of the barrel diameter. Possibly also, the observed conformation represents an on-pathway or off-pathway folding intermediate of apoM. The difference in fold topology is quite remarkable, and the fold promiscuity observed for m-apoM might possibly provide a glimpse at potential cross-points during the evolution of beta-barrels. (c) 2010 Elsevier Ltd. All rights reserved.},
  author       = {Sevvana, Madhumati and Kassler, Kristin and Ahnström, Josefin and Weiler, Sigrid and Dahlbäck, Björn and Sticht, Heinrich and Muller, Yves A.},
  issn         = {1089-8638},
  keyword      = {apolipoprotein,alternative conformations,misfolding,refolding,lipocalin},
  language     = {eng},
  number       = {3},
  pages        = {363--371},
  publisher    = {Elsevier},
  series       = {Journal of Molecular Biology},
  title        = {Mouse ApoM Displays an Unprecedented Seven-Stranded Lipocalin Fold: Folding Decoy or Alternative Native Fold?},
  url          = {http://dx.doi.org/10.1016/j.jmb.2010.09.062},
  volume       = {404},
  year         = {2010},
}