Most receptor-mediated signal transduction pathways in mammalian cells involve enzymes that generate either soluble or membrane-resident second messengers by modifying phospholipids present in cell membranes. These enzymes are activated in response to a variety of cellular signals such as hormones, cytokines and neurotransmitters.
We are trying to develop a detailed structural understanding of the network of interacting pathways involved in phospholipid signalling. Our current efforts focus on phosphoinositide 3-kinases and their downstream effectors. Due to their frequent mutation in human cancers, a structural understanding of heterodimeric PI3Ks is important for drug development.
Amongst many cellular processes regulated by specific phospholipid recognition is membrane protein sorting into multivesicular bodies (MVB) and macroautophagy, both of which are dependent on 3-phosphoinositides. We are determining the structures of endosomal protein complexes in order to understand their roles in cargo selection, localisation and inward membrane budding.
In addition to X-ray crystallography, we are using electron microscopy, protein engineering, biophysical methods and in vivo assays to characterise these regulatory interactions.