Institute of Structural Biology
University of Bonn

The binding and hydrolysis of ATP in NLRP3 remains a conundrum: The protein requires ATP for activation, but is not simply activated by excess of nucleotide; how nucleotide exchange is regulated is unclear, as is the correlation of ATP hydrolysis to protein activity. Rebecca and co-workers now analysed the nucleotide binding Walker A and Walker B motifs, sensors 1 and 2, Glu-switch and P-site for their implications in intrinsic hydrolysis and inflammasome activation. This is the first systematic analysis of ATP hydrolysis in STAND ATPases, showing that the correlation of hydrolysis activity to inflammation is multifaceted....

Up to 50% of the population carry a single nucleotide polymorphism (SNP) in the gene encoding the inflammasome sensor Nlrp1. This SNP causes an amino acid exchange from methionine 1184 to valine (M1184V), and has been associated with several autoimmune syndromes. In collaboration with the Masters lab (The Walter and Eliza Hall Institute, Melbourne) we provide a molecular basis for the effects of this variant. By comparing the wild-type and M1184V proteins, we show that the M1184V mutation stabilizes the FIIND domain in a monomeric conformation. For full-length NLRP1, this effect translates as a stabilization of a multimeric conformation. Furt...

There it is, the long awaited structure of a TRAP transporter. Our cryo EM structure of the sialic acid transporter HiSiaPQM finally reveals the function of the enigmatic Q-domain and how the membrane domains of TRAPs are structurally and conformationally coupled to their soluble substrate binding protein. This is the result of an eight years journey and a fantastic collaboration with Gavin Thomas from the University of York. As a cherry on the cake, single molecule studies with the lab of Uli Kubitscheck in Bonn provide the first real-time glimps of the transporter in action. The study has just been published in Nature Communications....