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

    Author
    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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    Mapping the Structural and Dynamic Determinants of pH-sensitive Heparin Binding to Granulocyte Macrophage-colony Stimulating Factor.pdf (2.568Mb)
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    Date Issued
    2020-09-29
    Subject
    Biology; Chemistry and chemical biology; Chemical and biological engineering; Biomedical engineering
    Degree
    Terms of Use
    In Copyright : this Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s). https://rightsstatements.org/page/InC/1.0/;
    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.
    Metadata
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    URI
    https://hdl.handle.net/20.500.13015/5389; https://doi.org/10.1021/acs.biochem.0c00538
    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; Note : if this item contains full text it may be a preprint, author manuscript, or a Gold OA copy that permits redistribution with a license such as CC BY. The final version is available through the publisher’s platform.
    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;
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