Histidine-Mediated pH-Sensitive Regulation of M-Ficolin:GlcNAc Binding in Innate Immunity Examined by Molecular Dynamics Simulations
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Yang-2011-Histidine-Mediated p.pdf
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Author(s)
Yang, Linfeng
Zhang, Jing
Ho, Bow
Ding, Jeak Ling
Date Issued
May 2011
Journal
PLoS ONE
Publisher
Public Library of Science
Citation
Yang, Lifeng et al. “Histidine-Mediated pH-Sensitive Regulation of M-Ficolin:GlcNAc Binding Activity in Innate Immunity Examined by Molecular Dynamics Simulations.” Ed. Ying Xu. PLoS ONE 6.5 (2011) : e19647.
Version
Final published version
Abstract
Background: M-ficolin, a pathogen recognition molecule in the innate immune system, binds sugar residues including N-acetyl-D-glucosamine (GlcNAc), which is displayed on invading microbes and on apoptotic cells. The cis and trans Asp282-Cys283 peptide bond in the M-ficolin, which was found to occur at neutral and acidic pH in crystal structures, has been suggested to represent binding and non-binding activity, respectively. A detailed understanding of the pH-dependent conformational changes in M-ficolin and pH-mediated discrimination mechanism of GlcNAc-binding activity are crucial to both immune-surveillance and clearance of apoptotic cells. Methodology/Principal Findings:
By immunodetection analysis, we found that the pH-sensitive binding of GlcNAc is regulated by a conformational equilibrium between the active and inactive states of M-ficolin. We performed constant pH molecular dynamics (MD) simulation at a series of pH values to explore the pH effect on the cis-trans isomerization of the Asp282-Cys283 peptide bond in the M-ficolin fibrinogen-like domain (FBG). Analysis of the hydrogen bond occupancy of wild type FBG compared with three His mutants (H251A, H284A and H297A) corroborates that His284 is indispensible for pH-dependent binding. H251A formed new but weaker hydrogen bonds with GlcNAc. His297, unlike the other two His mutants, is more dependent on the solution pH and also contributes to cis-trans isomerization of the Asp282-Cys283 peptide bond in weak basic solution. Conclusions/Significance:
Constant pH MD simulation indicated that the cis active isomer of Asp282-Cys283 peptide bond was predominant around neutral pH while the trans bond gradually prevailed towards acidic environment. The protonation of His284 was found to be associated with the trans-to-cis isomerization of Asp282-Cys283 peptide bond which dominantly regulates the GlcNAc binding. Our MD simulation approach provides an insight into the pH-sensitive proteins and hence, ligand binding activity.
MIT Department
Massachusetts Institute of Technology. Computational and Systems Biology Program
Singapore-MIT Alliance in Research and Technology (SMART)
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DOI of Published Version
https://doi.org/10.1371/journal.pone.0019647
