Institute of Structural Biology
University of Bonn

Our study on the type III CRISPR associated CalpL-T-S cascade has just been published in Nature. It’s an amazing story that started out of pure curiosity, when Christophe and Gregor decided to look into the structure and function of the enigmatic CalpL protease. The project really took off, when Niels joined the team and determined the crystal structure of CalpL alone and in complex with its activator cA4. Using bioinformatics, we figured out that the target of the protease is a small protein that we named CalpT. In a fantastic cooperation with the labs of Dmitri Svergun, Malcolm White, Bela Bode and Jonathan Schmid-Burgk we unraveled how the...

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 remains unclear, as is the correlation of ATP hydrolysis to protein activity. Rebecca, David 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...