A Structural Perspective of Innate Immunity: “The Devil is in the details”

SCAN Seminar

Title: A Structural Perspective of Innate Immunity 
         “The Devil is in the details”

Speaker: Colin Edward McVey

Affiliation: Protein Crystallography

Abstract:

NOD-like receptors (NLRs) comprise a family of cytosolic proteins that have been implicated as ancient cellular sentinels mediating protective immune responses elicited by intracellular pathogens or endogenous danger signals. NOD2, a prototypic NLR, is an intracellular sentinel of the innate immune response which was shown to recognize the bacterial cell wall component muramyl dipeptide. It has a tripartite domain structure enabling pathogen recognition, immune signalling and autoregulation.

Genetic variants in NOD2 domains have been associated with complex chronic inflammatory autoimmune diseases (e.g. Crohn’s disease & Blau syndrome). My current research is to study the protein interactions of NLRs and their role in the innate immune system. NLRs comprise a family of cytosolic proteins that have been implicated as ancient cellular sentinels mediating protective immune responses elicited by intracellular pathogens or endogenous danger signals. NOD2, a prototypic NLR,was shown to recognize the bacterial cell wall component muramyl dipeptide (MDP). It is the tripartite domain structure that gives rise to its promiscuous binding interactions, not untypical of proteins involved in signal transduction. My goal is to understand the interactions and modes of binding within signal transduction and regulation of NOD2 activation in the innate immune response with the aim to use X-ray crystallographic in conjunction with biochemical and biophysical methods to explore these interactions. The research focuses on murine NOD2 using a domain-by-domain approach to dissect the function and interactions of this intracellular immune receptor. A number of proteins have been purified that play a pivotal role in NOD2 functions, these will provide the platform to further elucidate and study the interactions in innate immune signalling.

Finally, we are studying viral proteins which are involved in modulation of cellular signalling pathways and viral latency. We focus on two gamma-herpesvirus proteins that play key but distinct roles in the viral latency program. One is an adaptor protein that manipulates cell signalling pathways through binding of Src homology domains. The other is an essential protein for latency that functions through the modulation of cellular transcriptional activity and viral DNA binding. Through structural and biophysical studies we  hope to elucidate the  function of these proteins.