Structure and Biology of GDNF Signalling Systems

Principal Investigators: ADRIAN GOLDMAN1, JIAWEI ZHOU2
Researcher: Veli-Matti Leppänen

1Institute of Biotechnology, University of Helsinki, Finland, 2Institute of Biochemistry and Cell Biology, Shanghai, China

GDNF and the three other GDNF family ligands (GFLs) are critical different aspects of neuronal development in the central and peripheral nervous systems. GDNF, for instance, protects dopamine neurons, making it a potential treatment for Parkinson's disease. GFLs signal through a receptor RET using co-receptors, called GFRas. On activation, RET signals cause cell survival, growth or differentiation. Permanently-active RET mutants cause various familial cancers, such as medullary thyroid carcinomas, while loss of RET function leads to Hirschsprung's disease.

How GFLs and their receptors work is still not properly understood. New GDNF receptors have recently been identified, including NCAM. In addition, a novel neuronal survival-promoting molecule, GRAL, related to GFRas, has also been chracterized. We also do not understand the molecular mechanisms of GFL:GFL-receptor interactions because of the lack of relevant structures.

We will thus study GFLs, GFL receptors and GFL:GFL-receptor complexes by binding studies and by x-ray crystallography to determine their structure. Furthermore, functional in vitro studies will be conducted in collaboration with Prof. Saarma's group, BI. In addition to binary complexes, we will also study ternary complexes, such as GDNF-GFRa1-RET. These studies will enable us to understand interactions and signalling in the GDNF system at atomic level. Furthermore, the complex structures will form the basis for rational drug design for the treatment of neurodegenerative diseases and RET-related cancer syndromes.

Contact: adrian.goldman(at)helsinki.fi, tel. +358 9 1915 8923