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Computational study of pH-dependent oligomerization and ligand binding in Alt a 1, a highly allergenic protein with a unique fold

Garrido-Arandia, María; Bretones, Jorge; Gómez-Casado, Cristina LU ; Cubells, Nuria; Díaz-Perales, Araceli and Pacios, Luis F. (2016) In Journal of Computer-Aided Molecular Design 30(5). p.365-379
Abstract

Alt a 1 is a highly allergenic protein from Alternaria fungi responsible for several respiratory diseases. Its crystal structure revealed a unique β-barrel fold that defines a new family exclusive to fungi and forms a symmetrical dimer in a butterfly-like shape as well as tetramers. Its biological function is as yet unknown but its localization in cell wall of Alternaria spores and its interactions in the onset of allergy reactions point to a function to transport ligands. However, at odds with binding features in β-barrel proteins, monomeric Alt a 1 seems unable to harbor ligands because the barrel is too narrow. Tetrameric Alt a 1 is able to bind the flavonoid quercetin, yet the stability of the aggregate and the own ligand binding... (More)

Alt a 1 is a highly allergenic protein from Alternaria fungi responsible for several respiratory diseases. Its crystal structure revealed a unique β-barrel fold that defines a new family exclusive to fungi and forms a symmetrical dimer in a butterfly-like shape as well as tetramers. Its biological function is as yet unknown but its localization in cell wall of Alternaria spores and its interactions in the onset of allergy reactions point to a function to transport ligands. However, at odds with binding features in β-barrel proteins, monomeric Alt a 1 seems unable to harbor ligands because the barrel is too narrow. Tetrameric Alt a 1 is able to bind the flavonoid quercetin, yet the stability of the aggregate and the own ligand binding are pH-dependent. At pH 6.5, which Alt a 1 would meet when secreted by spores in bronchial epithelium, tetramer-quercetin complex is stable. At pH 5.5, which Alt a 1 would meet in apoplast when infecting plants, the complex breaks down. By means of a combined computational study that includes docking calculations, empirical pKa estimates, Poisson–Boltzmann electrostatic potentials, and Molecular Dynamics simulations, we identified a putative binding site at the dimeric interface between subunits in tetramer. We propose an explanation on the pH-dependence of both oligomerization states and protein–ligand affinity of Alt a 1 in terms of electrostatic variations associated to distinct protonation states at different pHs. The uniqueness of this singular protein can thus be tracked in the combination of all these features.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Allergenic proteins, Electrostatic potentials, Ligand–protein docking, Molecular dynamics, Oligomerization, Protein–ligand binding
in
Journal of Computer-Aided Molecular Design
volume
30
issue
5
pages
15 pages
publisher
Kluwer
external identifiers
  • Scopus:84964337344
  • WOS:000378841100001
ISSN
0920-654X
DOI
10.1007/s10822-016-9911-6
language
English
LU publication?
yes
id
f0ec9bbd-5196-4463-9508-b4fff984446e
date added to LUP
2016-09-30 14:31:31
date last changed
2017-01-01 08:35:37
@article{f0ec9bbd-5196-4463-9508-b4fff984446e,
  abstract     = {<p>Alt a 1 is a highly allergenic protein from Alternaria fungi responsible for several respiratory diseases. Its crystal structure revealed a unique β-barrel fold that defines a new family exclusive to fungi and forms a symmetrical dimer in a butterfly-like shape as well as tetramers. Its biological function is as yet unknown but its localization in cell wall of Alternaria spores and its interactions in the onset of allergy reactions point to a function to transport ligands. However, at odds with binding features in β-barrel proteins, monomeric Alt a 1 seems unable to harbor ligands because the barrel is too narrow. Tetrameric Alt a 1 is able to bind the flavonoid quercetin, yet the stability of the aggregate and the own ligand binding are pH-dependent. At pH 6.5, which Alt a 1 would meet when secreted by spores in bronchial epithelium, tetramer-quercetin complex is stable. At pH 5.5, which Alt a 1 would meet in apoplast when infecting plants, the complex breaks down. By means of a combined computational study that includes docking calculations, empirical pKa estimates, Poisson–Boltzmann electrostatic potentials, and Molecular Dynamics simulations, we identified a putative binding site at the dimeric interface between subunits in tetramer. We propose an explanation on the pH-dependence of both oligomerization states and protein–ligand affinity of Alt a 1 in terms of electrostatic variations associated to distinct protonation states at different pHs. The uniqueness of this singular protein can thus be tracked in the combination of all these features.</p>},
  author       = {Garrido-Arandia, María and Bretones, Jorge and Gómez-Casado, Cristina and Cubells, Nuria and Díaz-Perales, Araceli and Pacios, Luis F.},
  issn         = {0920-654X},
  keyword      = {Allergenic proteins,Electrostatic potentials,Ligand–protein docking,Molecular dynamics,Oligomerization,Protein–ligand binding},
  language     = {eng},
  month        = {05},
  number       = {5},
  pages        = {365--379},
  publisher    = {Kluwer},
  series       = {Journal of Computer-Aided Molecular Design},
  title        = {Computational study of pH-dependent oligomerization and ligand binding in Alt a 1, a highly allergenic protein with a unique fold},
  url          = {http://dx.doi.org/10.1007/s10822-016-9911-6},
  volume       = {30},
  year         = {2016},
}