Histidine-Mediated pH-Sensitive Regulation of M-Ficolin:GlcNAc Binding 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...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | en_US |
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Public Library of Science
2011
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| Online Access: | http://hdl.handle.net/1721.1/65602 |
| _version_ | 1811072423827603456 |
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| author | Yang, Linfeng Zhang, Jing Ho, Bow Ding, Jeak Ling |
| author2 | Massachusetts Institute of Technology. Computational and Systems Biology Program |
| author_facet | Massachusetts Institute of Technology. Computational and Systems Biology Program Yang, Linfeng Zhang, Jing Ho, Bow Ding, Jeak Ling |
| author_sort | Yang, Linfeng |
| collection | MIT |
| 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. |
| first_indexed | 2024-09-23T09:05:44Z |
| format | Article |
| id | mit-1721.1/65602 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:05:44Z |
| publishDate | 2011 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/656022022-09-26T10:25:07Z Histidine-Mediated pH-Sensitive Regulation of M-Ficolin:GlcNAc Binding in Innate Immunity Examined by Molecular Dynamics Simulations Yang, Linfeng Zhang, Jing Ho, Bow Ding, Jeak Ling Massachusetts Institute of Technology. Computational and Systems Biology Program Singapore-MIT Alliance in Research and Technology (SMART) Yang, Linfeng Yang, Linfeng Ding, Jeak Ling 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. Singapore-MIT Alliance (Computational and Systems Biology) Singapore. Ministry of Education (MoE, T208B3109) 2011-09-02T14:26:59Z 2011-09-02T14:26:59Z 2011-05 2010-12 Article http://purl.org/eprint/type/JournalArticle 1932-6203 http://hdl.handle.net/1721.1/65602 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. en_US http://dx.doi.org/10.1371/journal.pone.0019647 PLoS ONE Creative Commons Attribution http://creativecommons.org/licenses/by/2.5/ application/pdf Public Library of Science PLoS |
| spellingShingle | Yang, Linfeng Zhang, Jing Ho, Bow Ding, Jeak Ling Histidine-Mediated pH-Sensitive Regulation of M-Ficolin:GlcNAc Binding in Innate Immunity Examined by Molecular Dynamics Simulations |
| title | Histidine-Mediated pH-Sensitive Regulation of M-Ficolin:GlcNAc Binding in Innate Immunity Examined by Molecular Dynamics Simulations |
| title_full | Histidine-Mediated pH-Sensitive Regulation of M-Ficolin:GlcNAc Binding in Innate Immunity Examined by Molecular Dynamics Simulations |
| title_fullStr | Histidine-Mediated pH-Sensitive Regulation of M-Ficolin:GlcNAc Binding in Innate Immunity Examined by Molecular Dynamics Simulations |
| title_full_unstemmed | Histidine-Mediated pH-Sensitive Regulation of M-Ficolin:GlcNAc Binding in Innate Immunity Examined by Molecular Dynamics Simulations |
| title_short | Histidine-Mediated pH-Sensitive Regulation of M-Ficolin:GlcNAc Binding in Innate Immunity Examined by Molecular Dynamics Simulations |
| title_sort | histidine mediated ph sensitive regulation of m ficolin glcnac binding in innate immunity examined by molecular dynamics simulations |
| url | http://hdl.handle.net/1721.1/65602 |
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