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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

In English

Författare

  • María Garrido-Arandia
  • Jorge Bretones
  • Cristina Gómez-Casado
  • Nuria Cubells
  • Araceli Díaz-Perales
  • Luis F. Pacios

Summary, in English

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.

Publiceringsår

2016-05-01

Språk

Engelska

Sidor

365-379

Publikation/Tidskrift/Serie

Journal of Computer-Aided Molecular Design

Volym

30

Issue

5

Dokumenttyp

Artikel i tidskrift

Förlag

Springer

Ämne

  • Medical Biotechnology

Nyckelord

  • Allergenic proteins
  • Electrostatic potentials
  • Ligand–protein docking
  • Molecular dynamics
  • Oligomerization
  • Protein–ligand binding

Status

Published

Forskningsgrupp

  • Mucosal Immunology

ISBN/ISSN/Övrigt

  • ISSN: 0920-654X