NLR effector domain interactions

Nod-like receptors (NLRs) are intracellular immune receptors implicated in innate immunity and inflammatory responses. The main function of NLRs is the specific recognition of bacterial as well as host derived danger signals, which leads to the initiation of host defence pathways. Moreover, the NLR family has gained increased attention, since polymorphisms in certain NLR genes result in chronic inflammatory diseases like Blau syndrome and Crohn`s disease. Despite intense research on NLR function, NLR signalling pathways are still fragmentary in molecular terms. Most importantly, detailed knowledge about the involved pyrin-pyrin (PYD:PYD) interactions is missing and underlying mechanistic principles remain largely elusive. Therefore, the proposed project specifically aims to: (1) highlight the molecular details of PYD:PYD complexes of NLRP1-ASC; NLRP2-ASC, POP1-ASC using DXMS (deuterium-exchange mass spectrometry) and NMR chemical shift experiments, and (2) to identify novel downstream interaction partners for NLRP1, NLRP2, and NLRP7 using TAP-tag technology. The proposed characterization of NLR effector domain/adaptor protein complexes as well as the identification of missing links within the NLR network will significantly further our mechanistic understanding of downstream signal transduction and uncover crucial components of NLR immune pathways.