The Guettler Lab

Divisions of Structural Biology and Cancer Biology

The Institute of Cancer Research

Lay Summary

Tissue stem cells are long-lived cells in our bodies that enable organs to regenerate. For example, the lining of our intestines fully renews over a course of 4-5 days, thanks to the function of stem cells nestled within the epithelium. These stem cells respond to particular external cues from their local environment that instruct them to divide and produce two different types of progeny cells. One daughter cell proceeds to develop into highly specialised gut cells. The other daughter cell maintains stem-cell characteristics. The latter process, known as stem cell “self-renewal”, also depends on the ability of these cells to maintain the ends of their chromosomes, the telomeres. (Note that in non-stem cells, telomeres shorten with every round of cell division, which causes these cells to age.) Intriguingly, stem cell maintenance mechanisms operate in many cancers, for example bowel cancer.

We take a multi-angled approach to understand the molecular details of stem cell maintenance. Structural biology, a discipline used to visualise cellular components at atomic or near-atomic detail, is at the heart of our work. In the same way as you can learn about the mechanisms of a machine by studying how it is built, you can learn about how proteins function by studying their detailed structures. With these insights in hand, we hope to uncover new ways to keep cancer cells in check.

We combine a range of approaches to understand the molecular details of how stem and cancer cells maintain their ability to divide over long periods of time. Structural biology teaches us about these processes at great detail. (Images modified from Mariotti et al., 2016)
We combine a range of approaches to understand the molecular details of how stem and cancer cells maintain their ability to divide over long periods of time. Structural biology teaches us about these processes at great detail. (Images modified from Mariotti et al., 2016)

Research Projects

Macromolecular acrobatics of tankyrase

The tankyrase proteins are part of a larger group of enzymes that can tag other proteins and themselves with elaborate, chain-like flags known as poly(ADP-ribose). To achieve that, tankyrase first needs to capture its targets, bring them into the correct orientation for tagging and then perform the tagging reaction itself. All these steps need to be carefully coordinated to prevent tankyrase from acting at the wrong time or in the wrong place. We aim to use sophisticated structural biology techniques to visualise the molecular details of tankyrase in action. We next probe new insights from this work by performing experiments in human tissue culture cells. Together with chemists, we also aim to develop novel ways of artificially modulating tankyrase with drug-like molecules to learn more about its function. 

Proteins consist of modules (“domains”) that fulfil specialised functions. In tankyrase, so-called ankyrin repeat clusters (ARCs) recognise particular features in other proteins, enabling tankyrase to communicate with these proteins. In some cases, this requires the formation of large beads-on-a-string structures that arise from the mutual interaction of many tankyrase molecules via their sterile alpha motif (SAM) domains. A biochemical tagging reaction known as poly(ADP-ribosyl)ation is performed by a catalytic PARP domain. (Images modified from Guettler et al., 2011; Mariotti et al., 2016 and Pollock et al., 2017)
Proteins consist of modules (“domains”) that fulfil specialised functions. In tankyrase, so-called ankyrin repeat clusters (ARCs) recognise particular features in other proteins, enabling tankyrase to communicate with these proteins. In some cases, this requires the formation of large beads-on-a-string structures that arise from the mutual interaction of many tankyrase molecules via their sterile alpha motif (SAM) domains. A biochemical tagging reaction known as poly(ADP-ribosyl)ation is performed by a catalytic PARP domain. (Images modified from Guettler et al., 2011; Mariotti et al., 2016 and Pollock et al., 2017)

How do key signalling proteins in stem and cancer cells collaborate?

Proteins do not exist in isolation. Most proteins are social and function in the context of multi-protein complexes, in which different members collaborate with each other to achieve a common goal. We aim to understand the precise details of how complexes relevant to stem and cancer cells operate. We take a particular interest in learning about how tankyrase can modulate such complexes.

The beta-catenin destruction complex is an example for collaborative proteins. The complex is bossed around by tankyrase; we aim to understand how. (Images modified from Mariotti et al., 2017)
The beta-catenin destruction complex is an example for collaborative proteins. The complex is bossed around by tankyrase; we aim to understand how. (Images modified from Mariotti et al., 2017)