Histidine-mediated pH-sensitive regulation of M-ficolin:GlcNAc binding activity in innate immunity examined by molecular dynamics simulations.

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...

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Main Authors: Lifeng Yang, Jing Zhang, Bow Ho, Jeak Ling Ding
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2011-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC3088710?pdf=render
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author Lifeng Yang
Jing Zhang
Bow Ho
Jeak Ling Ding
author_facet Lifeng Yang
Jing Zhang
Bow Ho
Jeak Ling Ding
author_sort Lifeng Yang
collection DOAJ
description 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.
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spelling doaj.art-65569fab4ac14304a9d57c8275fa57b32022-12-21T19:16:17ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-0165e1964710.1371/journal.pone.0019647Histidine-mediated pH-sensitive regulation of M-ficolin:GlcNAc binding activity in innate immunity examined by molecular dynamics simulations.Lifeng YangJing ZhangBow HoJeak Ling DingBACKGROUND: 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.http://europepmc.org/articles/PMC3088710?pdf=render
spellingShingle Lifeng Yang
Jing Zhang
Bow Ho
Jeak Ling Ding
Histidine-mediated pH-sensitive regulation of M-ficolin:GlcNAc binding activity in innate immunity examined by molecular dynamics simulations.
PLoS ONE
title Histidine-mediated pH-sensitive regulation of M-ficolin:GlcNAc binding activity in innate immunity examined by molecular dynamics simulations.
title_full Histidine-mediated pH-sensitive regulation of M-ficolin:GlcNAc binding activity in innate immunity examined by molecular dynamics simulations.
title_fullStr Histidine-mediated pH-sensitive regulation of M-ficolin:GlcNAc binding activity in innate immunity examined by molecular dynamics simulations.
title_full_unstemmed Histidine-mediated pH-sensitive regulation of M-ficolin:GlcNAc binding activity in innate immunity examined by molecular dynamics simulations.
title_short Histidine-mediated pH-sensitive regulation of M-ficolin:GlcNAc binding activity in innate immunity examined by molecular dynamics simulations.
title_sort histidine mediated ph sensitive regulation of m ficolin glcnac binding activity in innate immunity examined by molecular dynamics simulations
url http://europepmc.org/articles/PMC3088710?pdf=render
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AT jingzhang histidinemediatedphsensitiveregulationofmficolinglcnacbindingactivityininnateimmunityexaminedbymoleculardynamicssimulations
AT bowho histidinemediatedphsensitiveregulationofmficolinglcnacbindingactivityininnateimmunityexaminedbymoleculardynamicssimulations
AT jeaklingding histidinemediatedphsensitiveregulationofmficolinglcnacbindingactivityininnateimmunityexaminedbymoleculardynamicssimulations