Researchers at the MRC-Laboratory of Molecular Biology (MRC-LMB) and the Babraham Institute have worked together to solve the structure of an important signalling complex which is known to be involved in nutrition and disease. Knowing the structure of a molecule helps greatly with understanding how it works and also helps the design of drugs to target the molecule and modify its activity. The description of the structure is published in the journal Science.
The complex, called Vps34 endosomal complex II, makes one of the key signalling molecules in the cell, PI3P. This molecule acts as the cell’s traffic controller, directing small cellular structures called vesicles to their correct destination in the cell.
Crystallising protein complexes is more difficult than working out the structure of a lone molecule as the subunits of the complex need to remain associated with each other through the crystallisation process in order to give an accurate picture of how they fit together and the shape of the complex overall.
The crystallisation process revealed a Y-shaped structure and provided many details about the intricacies of the complex. The research answers important questions on how the different subunits interact, the roles they play and how the complex recognises cellular membranes in order to make PI3P.
As a result of this new knowledge, it will now be possible to design molecules that specifically interfere with the function of the complex, which may become the basis for novel therapeutics.
Dr Nicholas Ktistakis, group leader in the Institute’s Signalling programme and senior author on the paper, said: “The Vps34 complex is essential for two important physiological functions that keep cells healthy: endocytosis and autophagy. Endocytosis is important during normal growth and it is regulated by complex II, while autophagy allows cells and organisms to survive when nutrients are scarce and is regulated by complex I. Discovering the structure of complex II has allowed us to understand how it carries out its functions during endocytosis and to imagine how complex I works during autophagy.
“The elucidation of the structure represents how fundamental research has the potential to contribute to improvements in health and understanding disease. I’m very grateful for the support of the funders, in particular the BBSRC who supported my contribution to this work.”
Dr Roger Williams, group leader at the MRC-LMB and senior author on the paper, said: “The structure of this complex represents the culmination of approximately five year’s work in our lab and 25 year’s work worldwide on understanding the function of this key component of intracellular sorting. This complex is essential for sorting of cellular cargo, autophagy and cell division and consequently is a target of widespread efforts to develop pharmaceuticals that would enhance autophagy to treat or prevent diseases such as Huntington’s, Alzheimer’s, ALS and types of dementia.”
This work was funded by the Biotechnology and Biological Science Research Council and the Medical Research Council.
Nicholas Ktistakis, group leader, Signalling programme
LMB Insight on Research: Structure of the endosomal Vps34 complex II reveals insights into its function
As a publicly funded research institute, the Babraham Institute is committed to engagement and transparency in all aspects of its research. The research presented here used a llama to produce complex II-specific antibodies (nanobodies). The antibodies were obtained from a commercial source.
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Rostislavleva & Soler et al. (2015) Structure and flexibility of the endosomal Vps34 complex reveals the basis of its function on membranes. Science
09 October 2015