Altered Backbone and Side-Chain Interactions Result in Route Heterogeneity during the Folding of Interleukin-1 beta (IL-1 beta)

作者：Capraro Dominique T; Lammert Heiko; Heidary David K; Roy Melinda; Gross Larry A; Onuchic Jose N; Jennings Patricia A^*

来源：Biophysical Journal, 2013, 105(4): 975-983.

DOI：10.1016/j.bpj.2013.06.019

Deletion of the beta-bulge trigger-loop results in both a switch in the preferred folding route, from the functional loop packing folding route to barrel closure, as well as conversion of the agonist activity of IL-1 beta into antagonist activity. Conversely, circular permutations of IL-1 beta conserve the functional folding route as well as the agonist activity. These two extremes in the folding-functional interplay beg the question of whether mutations in IL-1 beta would result in changes in the populations of heterogeneous folding routes and the signaling activity. A series of topologically equivalent water-mediated beta-strand bridging interactions within the pseudosymmetric beta-trefoil fold of IL-1 beta highlight the backbone water interactions that stabilize the secondary and tertiary structure of the protein. Additionally, conserved aromatic residues lining the central cavity appear to be essential for both stability and folding. Here, we probe these protein backbone-water molecule and side chain-side chain interactions and the role they play in the folding mechanism of this geometrically stressed molecule. We used folding simulations with structure-based models, as well as a series of folding kinetic experiments to examine the effects of the F42W core mutation on the folding landscape of IL-1 beta. This mutation alters water-mediated backbone interactions essential for maintaining the trefoil fold. Our results clearly indicate that this perturbation in the primary structure alters a structural water interaction and consequently modulates the population of folding routes accessed during folding and signaling activity.

• 出版日期2013-8-20