Mapping the Structural and Dynamic Determinants of pH-sensitive Heparin Binding to Granulocyte Macrophage-colony Stimulating Factor

Authors
Cui, Jennifer Y.
Zhang, Fuming
Nierzwicki, Lukasz
Palermo, Giulia
Linhardt, Robert J.
Lisi, George P.
ORCID
https://orcid.org/0000-0003-2219-5833
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Issue Date
2020-09-29
Keywords
Biology , Chemistry and chemical biology , Chemical and biological engineering , Biomedical engineering
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Full Citation
Mapping the Structural and Dynamic Determinants of pH-sensitive Heparin Binding to Granulocyte Macrophage-colony Stimulating Factor, J. Y. Cui, F. Zhang, L. Nierzwicki, G. Palermo, R. J. Linhardt, G. P. Lisia, Biochemistry, 59, 3541−3553, 2020.
Abstract
Granulocyte macrophage colony stimulating factor (GMCSF) is an immunomodulatory cytokine that is harnessed as a therapeutic. GMCSF is known to interact with other clinically important molecules, such as heparin, suggesting that endogenous and administered GMCSF has the potential to modulate orthogonal treatment outcomes. Thus, molecular level characterization of GMCSF and its interactions with biologically active compounds is critical to understanding these mechanisms and predicting clinical consequences. Here, we dissect the biophysical factors that facilitate the GMCSF–heparin interaction, previously shown to be pH-dependent, using nuclear magnetic resonance spectroscopy, surface plasmon resonance, and molecular dynamics simulations. We find that the affinity of GMCSF for heparin increases not only with a transition to acidic pH but also with an increase in heparin chain length. Changes in local flexibility, including a disruption of the N-terminal helix at acidic pH, also accompany the binding of heparin to GMCSF. We use molecular dynamics simulations to propose a mechanism in which a positive binding pocket that is not fully solvent accessible at neutral pH becomes more accessible at acidic pH, facilitating the binding of heparin to the protein.
Description
Biochemistry, 59, 3541−3553
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Department
The Linhardt Research Labs.
The Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies (CBIS)
Publisher
American Chemical Society (ACS)
Relationships
The Linhardt Research Labs Online Collection
Rensselaer Polytechnic Institute, Troy, NY
Biochemistry
https://harc.rpi.edu/
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A full text version is available in DSpace@RPI