Control and enzymatic activation of the APC/C ubiquitin ligase system

We study a cellular enzyme that plays a key role in selective protein destruction: the anaphase-promoting complex/cyclosome (APC/C). The APC/C controls many events including genome DNA duplication and segregation, cell growth, differentiation and death, DNA damage repair, brain and metabolic functions. Greater understanding of APC/C function will be of great benefit to human health. Although 20 years have passed since its discovery, our understanding of APC/C function and control is lamentably limited. This is partly due to the sheer size and complexity of the enzyme. The APC/C comprises 14 subunits, many of which are chemically modified at multiple sites by the addition and removal of phosphate groups. Very little is known about the control of these cycles of chemical modification.

We have developed an approach that can now be used to study these controls. We reconstitute the entire APC/C enzyme by making the subunits in a surrogate production system. We then study the function of these reconstituted APC/C complexes in extracts from frog eggs.

This programme will extend these studies to define more precisely how the APC/C is controlled by phosphorylation, identify new binding partners and map the changes in APC/C structure that accompany activity.