NLR-proteins in Immunity and Inflammation
Despite their importance, the ligands, specificity and mechanisms of most NLRs are unknown. In order to identify their physiology and respective roles in human infections and inflammatory diseases, we will characterize the function of NLRs by biochemical and structural means. Functional analysis is the key to understanding the molecular mechanisms of disease and represents the new front-line and limiting factor for realizing potential benefits of genome-based science and stem cell research. Using an integrative and parallelized approach, Robert Schwarzenbacher and his colleagues contributed functional studies in the fields of immunity (EMBO J 1999), apoptosis (Cell 2000), enzymology (PNAS 2004), as well as drug discovery (Nat. Struct. Mol. Biol. 2004).
Moreover, they recently unravelled the structure and function of the apoptotic protease activating factor 1 (Apaf-1) (Nature 2005), the first prototype of huge signalling platforms and a close relative of NLRs. Prof. Schwarzenbacher will bring his unique expertise in functional characterization and high throughput methodology gained at the Joint Centre for Structural Genomics back to Salzburg to create a new European centre of excellence. A primary goal of his team is to generate a platform for the development and application of functional studies in order to understand signal proteins and their complexes involved in disease and to use this information for the development of novel therapies.
PARIS LODRON UNIVERSITÄT SALZBURG
Anna Maria FRISCHAUF (Prof.)
NLRS IN IMMUNITY
Grant agreement ID: 33534
1 October 2006
30 September 2010
PARIS LODRON UNIVERSITÄT SALZBURG
Final Activity Report Summary - NLRS IN IMMUNITY (NLR-proteins in Immunity and Inflammation)
The team created a platform for the development and application of functional studies in order to understand NLR signalling proteins and their complexes involved in disease. This information is the key for the development of novel therapies. Using an integrative and parallelized approach, the team successfully established a library of all human NLR proteins suitable for structural and functional studies. This resource is shared with the international scientific community to ensure effective networking and rapid progress in the field. Genome wide interaction screens of NLRs revealed novel interaction partners in inflammatory, apoptotic and developmental signalling pathways.
Structural studies of NLRP7, NLRP12, NLRP4, NLRC5, NLRP14 and NLRP10 and interaction studies with signalling partners like ASC, ASC2 and RICK shed new light on the transient nature of NLR effector domain interactions. Moreover, the team unraveled the NLR effector domain signalling mechanism and published this work entitled "The Fas/FADD death domain complex structure unravels signalling by receptor clustering" in Nature. Structural studies on NLRP10 reveal a first glimpse of the NLRP10 inflammasome which follows the heptameric structure of the apoptosome. Functional studies reveal that NLRP7 is involved in the wnt-signalling pathway explaining its role in developmental disorders.
Results have already been published in 16 scientific articles with another 10 to follow in the near future. Last but not least the main goal of this MCEXT grant, namely to bring an excellent research team back from the USA and to ensure its establishment in Europe has been an outstanding success.
Deliverables not available
Publications not available