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On the Structure and Dynamics of IL-36Ra, a Key Player in Psoriatic and Inflammatory Diseases


Interleukin-36 receptor antagonist is a cytokine that recently has been implicated in psoriatic diseases. Genome wide association studies observed single point mutations in the IL36RN gene which were associated with psoriasis patients. Characterizing how IL-36Ra works at a molecular level is critical in determining how diseases states may arise. Two observations regarding IL-36Ra were studied in detail in this work. Firstly, IL-36Ra was observed to be highly sensitive to N-terminal cleavage, in that the removal of the initiator methionine can activate the cytokine to its full activity. Secondly, IL-36Ra contains a unique disulfide bond that is not found in any related family member.

Chapter 3 details the NMR (Nuclear Magnetic Resonance) assignments of IL-36Ra necessary to solve the solution structure and probe phenomena at a residue resolution.

Chapter 4 details our observations of the structural changes and dynamics changes in IL-36Ra when comparing full length IL-36Ra to the N-terminal methionine cleaved IL-36Ra. Using a combination of NMR and hydrogen/deuterium we observed subtle differences in the two isoforms. The structural studies implicated the barrel structure in allowing allosteric transmission from N-terminal face to the opposite side of the molecule. Additionally, our dynamics studies revealed changes in the motions of the loops in the cap of the protein that are responsible for receptor binding. The changes were likely mediated via the residues at the cap-barrel interface which allowed changes in the barrel architecture to affect the loops in the cap subdomain.

Chapter 5 details our observations of the structural changes as well as dynamics changes in IL-36Ra when comparing oxidized IL-36Ra to the reduced IL-36Ra. Our data shows that the reduced form is highly destabilized overall, and specifically in the strands local to the disulfide bond. However, H/D exchange revealed that the residue diametrically opposed to the disulfide increased in protection from exchange, whereas most other residues decreased after the removal of the disulfide bond. These observations allowed us to construct a model in which the barrel expands without the presence of a disulfide

Lastly, Chapter 6 details the changes in H/D protection when IL-36Ra interacts with its receptor IL-36R. Different exchange profiles were observed for the two N-terminal isoforms when interacting with IL-36R. Using the observations, we were able to build a model in which the fully active IL-36Ra likely tunes the receptor off rate through the N-terminal/2nd trefoil interface that does not exist in the less active isoform.

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