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Abstract
Cytokines are key mediators of cellular communication and regulators of biological advents. The timing, quantity and localization of cytokines are key features in producing specific biological outcomes, and thus have been thoroughly studied and reviewed while continuing to be a focus of the cytokine biology community. Due to the complexity of cellular signaling and multitude of factors that can affect signaling outcomes, systemic level studies of cytokines are ongoing. Despite their small size, cytokines can exhibit structurally promiscuous and dynamic behavior that plays an equally important role in biological activity. In this review using case studies, we highlight the recent insight gained from observing cytokines through a molecular lens and how this may complement a system-level understanding of cytokine biology, explain diversity of downstream signaling events, and inform therapeutic and experimental development.
Highlights
Cytokines are small signaling proteins that serve as effectors of immunity and require spatial or temporal expression to regulate biological outcomes (Altan-Bonnet and Mukherjee, 2019)
Such insight can inform 1) the role played by cytokines as agents of cellular communication, 2) the improvement of tools leveraged for research, and 3) the development of cytokines as therapeutics or targets in clinical treatment plans
The authors propose that these structural fluctuations are likely to affect binding affinity to receptor A, providing insight into the activation of receptor signaling based on atomic level dynamics that cannot be resolved from systems level observations examining only the presence and quantity of IL-17
Summary
Cytokines are small signaling proteins that serve as effectors of immunity and require spatial or temporal expression to regulate biological outcomes (Altan-Bonnet and Mukherjee, 2019). NMR chemical shifts mapped the heparin binding site and relaxation experiments, supported by molecular simulations, confirmed a high level of conformational flexibility along the binding interface and proposed a model for the complex structure (Figure 1C) This binding interaction is dependent on the accessibility of the binding pocket, but the size of the heparin as well, where heparins able to span the anchor points at the histidine triad (Figure 1D) and the adjacent flexible linker with several lysine residues bind with greater affinity than smaller chain heparins. This work reinforced an important aspect of cytokine biochemistry that is intimately tied to the hypothesized dynamic mechanisms of action; the utility of conducting biophysical studies in regimes beyond those of “ideal” conditions In this case, if GMCSF were only characterized based on its presence in a certain niche (i.e. a microenvironment at neutral pH mimicking only circulating GMCSF), the resulting biochemical outcomes would not have captured its high affinity state for heparin and a gap in our understanding of its mechanism(s) would remain. The authors propose that these structural fluctuations are likely to affect binding affinity to receptor A (but not other IL-17 receptors), providing insight into the activation of receptor signaling based on atomic level dynamics that cannot be resolved from systems level observations examining only the presence and quantity of IL-17
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