Scheme: Wolfson Research Merit Awards
Organisation: University of Leeds
Dates: Aug 2013-Jul 2018
Summary: Our focus is on membrane-associated or integral membrane proteins, and on complexes, in particular: (1) understanding complement down-regulation by factor H; (2) understanding the structure and mechanism of integral membrane pyrophosphatases (published in Science in 2012); and (3) understanding how GDNF signals through the Ret receptor tyrosine kinase.
On complement, our structures provided a novel model of how factor H binds glycosylaminoglycans and C3d/C3b simultaneously. This leads to recruitment of factor I, cleavage of C3b, and so down-regulation. Our work explained why failures in this system, either due to STEC infection or mutations in factor H, cause (atypical) haemolytic uremic syndrome (HUS). Atypical HUS leads to acute renal failure. Our work on the membrane pyrophosphatase revealed a completely new protein architecture and mechanism for coupling PPi hydrolysis to ion pumping. We are now focusing on structures of the protozoan parasite enzymes.
Finally, our work on GDNF has revealed how it binds its cofactor, GFRa1, and how this leads to measurable differences in internal Ret signalling and led to the first models of the Ret binding surface on GFRa1. Our focus is now on structures and biophysical/cell biological understanding of Ret signalling. This requires large amounts of Ret, which, unlike other laboratories, we have been able to purify in active form, and have been able to obtain initial crystals.