Glycan-mediated Functional Assembly of IL-1RI: Structural Insights into
Completion of the Current Description for Immune Response
Abstract
Interleukin 1 receptor type I (IL-1RI) is a transmembrane receptor that
triggers the inflammatory response. Understanding its detailed mechanism
of action is crucial for treating immune disorders. IL-1RI is activated
upon the formation of its “functional assembly” that occurs by binding
of the cytokine and the accessory protein (IL-1RAcP) to the receptor.
Glycosylation of the IL-1RI and IL-1RAcP play critical roles in the
activation process. Here, extensive classical and accelerated molecular
dynamics simulations are carried out to examine the structural role of
glycosylation in the arrangement of the functional assembly at the
atomic level. It is shown that the assembly is built in two types of
non-signalling and signalling forms with the latter being the most
frequently occurring form. The non-signalling assembly is formed by
binding of the compact conformation of the glycosylated IL-1RI to the
IL-1RAcP. In this type of assembly, the IL-1R is not accessible to the
cytokines and thus it is unable to send signals to the cell. The
signalling assembly is formed by binding of the extended glycosylated
IL-1RI to the accessory protein. This assembly is locked in the extended
form by persistent hydrogen bonds within and between the interconnected
glycans of IL-1RI and IL-1RAcP. Cytokine binding site of the IL-1RI
extracellular domain is exposed in this type of assembly and the signals
could be transported to the cell. Moreover, contrary to the experimental
interpretations, in both types of the assembly, binding of the IL-1RAcP
to IL-1RI is primary to the cytokine binding to the complex.