Mapping the Structural and Dynamic Determinants of pH-Sensitive Heparin Binding to Granulocyte Macrophage Colony Stimulating Factor - Publikacja - MOST Wiedzy

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

Abstrakt

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.

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Kategoria:
Publikacja w czasopiśmie
Typ:
artykuły w czasopismach
Opublikowano w:
BIOCHEMISTRY-US nr 59, strony 3541 - 3553,
ISSN: 0006-2960
Język:
angielski
Rok wydania:
2020
Opis bibliograficzny:
Cui J., Zhang F., Nierzwicki Ł., Palermo G., Linhardt R., Lisi G.: Mapping the Structural and Dynamic Determinants of pH-Sensitive Heparin Binding to Granulocyte Macrophage Colony Stimulating Factor// BIOCHEMISTRY-US -Vol. 59,iss. 38 (2020), s.3541-3553
DOI:
Cyfrowy identyfikator dokumentu elektronicznego (otwiera się w nowej karcie) 10.1021/acs.biochem.0c00538
Weryfikacja:
Politechnika Gdańska

wyświetlono 111 razy

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