Structural basis of tankyrase activation by polymerization.
Pillay N, Mariotti L, Zaleska M, Inian O, Jessop M, Hibbs S, Desfosses A, Hopkins PCR, Templeton CM, Beuron F, Morris EP, Guettler S
Nature, 2022
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It all starts with protein purification.
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Science and large rodents ...
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We study the architecture of protein complexes using cryo-electron microscopy.
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We use X-ray crystallography to study protein function in signal transduction.
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A foggy day in London Town.
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TNKS2 SAM domain filaments: some signalling proteins polymerise to switch functional states.
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We aim to reconstitute signalling complexes from purified proteins to recapitulate their activities in the cell.
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Punctate subcellular localisation reflects polymerisation of this signalling protein.
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We use structural and biochemical information to interrogate protein function in cells.
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Happy pipetting!
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We have used X-ray crystallography to reveal the mechanism of tankyrase polymerisation.
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X-ray crystallography provides detailed insights into protein mechanisms.
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Our lab is located at the Chelsea site of ICR in central London. This is the view from the top floor.
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A GPU system for our cryo-EM work: of course the coolant had to be green.
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Our neighbours: the Natural History and Victoria & Albert Museums.
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Weiter forschen - keep researching!
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Cryo-EM map of a tankyrase filament.
Using Structural Biology to Understand Cell Signalling
Welcome to the Guettler Lab! We employ biochemistry, structural biology and cell biology to study the molecular mechanisms of Wnt/beta-catenin signalling and telomere homeostasis, with a particular focus on how poly(ADP-ribosyl)ation (PARylation) controls both processes. Besides understanding fundamental mechanisms of cell function, we aim to uncover novel potential therapeutic avenues in cancer.Selected Publications
View all »Reconstitution of the destruction complex defines roles of AXIN polymers and APC in β-catenin capture, phosphorylation, and ubiquitylation.
Ranes M, Zaleska M, Sakalas S, Knight R, Guettler S
Molecular Cell, 2021
View on PubMed »ADP-ribosyltransferases, an update on function and nomenclature.
Lüscher B, Ahel I, Altmeyer M, Ashworth A, Bai P, Chang P, Cohen M, Corda D, Dantzer F, Daugherty MD, Dawson TM, Dawson VL, Deindl S, Fehr AR, Feijs KLH, Filippov DV, Gagné JP, Grimaldi G, Guettler S, Hoch NC, Hottiger MO, Korn P, Kraus WL, Ladurner A, Lehtiö L, Leung AKL, Lord CJ, Mangerich A, Matic I, Matthews J, Moldovan GL, Moss J, Natoli G, Nielsen ML, Niepel M, Nolte F, Pascal J, Paschal BM, Pawłowski K, Poirier GG, Smith S, Timinszky G, Wang ZQ, Yélamos J, Yu X, Zaja R, Ziegler M
The FEBS Journal, 2021
View on PubMed »Fragment-based screening identifies molecules targeting the substrate-binding ankyrin repeat domains of tankyrase.
Pollock K, Liu M, Zaleska M, Meniconi M, Pfuhl M, Collins I, Guettler S
Scientific Reports, 2019, 9 (1), 19130
View on PubMed »Solution NMR assignment of the ARC4 domain of human tankyrase 2.
Zaleska M, Pollock K, Collins I, Guettler S, Pfuhl M
Biomolecular NMR Assignments, 2019
View on PubMed »Structural Basis for Auto-Inhibition of the NDR1 Kinase Domain by an Atypically Long Activation Segment.
Xiong S, Lorenzen K, Couzens AL, Templeton CM, Rajendran D, Mao DYL, Juang YC, Chiovitti D, Kurinov I, Guettler S, Gingras AC, Sicheri F
Structure (London, England : 1993), 2018, 26 (8), 1101-1115.e6
View on PubMed »Regulation of Wnt/β-catenin signalling by tankyrase-dependent poly(ADP-ribosyl)ation and scaffolding.
Mariotti L, Pollock K, Guettler S
British Journal of Pharmacology, 2017, 174 (24), 4611-4636
View on PubMed »Identifying and Validating Tankyrase Binders and Substrates: A Candidate Approach.
Pollock K, Ranes M, Collins I, Guettler S
Methods in Molecular Biology (Clifton, N.J.), 2017, 1608, 445-473
View on PubMed »Tankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-β-Catenin Signaling.
Mariotti L, Templeton CM, Ranes M, Paracuellos P, Cronin N, Beuron F, Morris E, Guettler S
Molecular Cell, 2016, 63 (3), 498-513
View on PubMed »AXIN Shapes Tankyrase ARChitecture.
Guettler S
Structure (London, England : 1993), 2016, 24 (10), 1625-1627
View on PubMed »Latest News
View all »Cryo-EM reveals structural basis of tankyrase activation by polymerisation
In our latest paper, we report structure-function studies that reveal how tankyrase is turned from a sluggish to an active protein by filamentous polymerisation. You can read the open-access paper here. The paper comes with a press release by ICR. Congratulations to the team!
Postdoc position available
We have a Postdoc position available, with a project centred on studying the mechanisms of site-specific ADP-ribosylation in Wnt/beta-catenin signalling and telomere maintenance. Details can be found here. The application period closes on the 6th of November 2022.
PhD Studentship in Medicinal Chemistry
Come and join us! We have an MRC iCASE PhD Studentship available in our team. In collaboration with AstraZeneca, you will develop novel means to probe the function of one of our favourite proteins. More information can be found here. Application deadline is the 13th of November 2022.
Welcome Shafayat!
We welcome Shafayat Azad to our team. Shaf joins us as a PhD Student and will investigate the mechanisms of telomere maintenance.
Michael speaks at “Black in Cancer”
Michael Ranes speaks at the inaugural “Black in Cancer” conference – an international collaboration between Black in Cancer and Cancer Research UK, one of our major funders.
Team Member Yexin Xie receives her PhD
Last month, we celebrated Yexin’s PhD graduation. Many congratulations Yexin on your well-deserved PhD, and all the best for your next steps!
Thank you and goodbye to Nisha!
After almost three years in the lab, Nisha is moving on. We say thank you and goodbye – all the best for the future! Stay tuned for exciting publication news coming soon.
Farewell Euan!
We say thank you and farewell to Euan Colaco Osorio, who joined us for almost two months as a Summer Student funded by the Lister Institute. All the best for your next adventure!
Iona awarded poster prize at American Chemical Society Medicinal Chemistry Symposium
PhD Student Iona Black has has been awarded the Best Poster prize at the 37th American Chemical Society Medicinal Chemistry Symposium held in New York City in June 2022. To attend the conference, Iona received a Royal Society of Chemistry researcher development grant of £500. Many congratulations Iona!
2022 Lab Retreat in Hastings
Our first lab retreat in a long time: two days of science and sunshine … and lots of food.
PhD studentship available
A fully funded PhD studentship on the mechanisms of telomere protection and length homeostasis is available in our team. For details and to apply, check out the ICR website. Application deadline is the 14th of November 2021.
Destruction complex reconstitution among ten featured ICR achievements of 2021
Our reconstitution of the beta-catenin destruction complex made it to ICR’s ten featured scientific achievements of 2021. What a nice way to end the lab year and a real testament to the team’s work! You can find all research highlights on the ICR website.
#BlackinCancer: Reaching communities most affected by prostate cancer
For Black in Cancer Week, ICR’s Science Communications Officer Juanita Bawagan spoke to our team member Dr Michael Ranes about the importance of diversity in cancer research for science and society. You can read the article here.
Michael speaks at the UNC Cancer Network
Our Postdoc Michael Ranes will present his work at the University of North Carolina (UNC) Lineberger Comprehensive Cancer Center. Here are the seminar details:
“Molecular mechanisms of Wnt signaling: reducing complexity”.
https://unccn.zoom.us/webinar/register/WN_2oM9nhM8Sz-xBL9QgGuXCg/
Sep 22, 2021 11:00 AM in Eastern Time (US and Canada)
Our latest paper hits the ICR news.
The ICR has featured our latest paper in its news stream on the ICR website.
Meet the authors: Michael and Sebastian speak with Molecular Cell about the story behind our latest paper.
We spoke with Molecular Cell about our latest paper, “Reconstitution of the destruction complex defines roles of AXIN polymers and APC in β-catenin capture, phosphorylation, and ubiquitylation,” personal experiences in science, our lab’s research and the people behind our science. Read the interview here.
New paper: biochemical reconstitution of the beta-catenin destruction complex
Our latest paper, reporting the biochemical reconstitution of the beta-catenin destruction complex, is now published online. Congratulations to Michael, Mariola, Saira and Ruth! You can find the open access article here.
ICR survey gives insight into the impact of the COVID-19 pandemic on cancer research
The Institute of Cancer Research surveyed 239 of its researchers to gain insights into the impact of the COVID-19 pandemic on their research, and to point to possible solutions. Read the results here.
New electron microscopy infrastructure
Exciting news: our new Glacios cryo-electron microscope has arrived and is being installed. The photo pictures Basil Greber, a new Team Leader in the Division of Structural Biology, with the microscope in its new home. A new era of Structural Biology at the ICR!
Welcome Saira, Ben and Giacomo!
In October, we welcomed three new PhD students to the lab: Saira, Ben and Giacomo! Exciting times!
Kick-starting the ICR: an interview with PhD student Iona Black
Iona Black, PhD student in the lab, has been interviewed as part of the #KickstartICR appeal. You can read the interview here. To learn more about how you can help ICR to kick-start research after lockdown, please visit the Kick-Start Appeal website.
Back to the lab …
We are back to the lab since June, with a rotation system to limit occupancy, but our research can go on. Our recent (socially distanced) lab picnic in the nearby Hyde Park was a nice summer treat.
Welcome Lucie, Paul and Matthew!
We recently welcomed three new team members: Lucie Vyletova and Paul Hopkins join us for some time as Higher Scientific Officers. Matthew Jessop started his postdoctoral research. Welcome Lucie, Paul and Matthew!
The team is growing.
Today we welcome our new Postdoctoral Fellow Nisha Pillay to the group. Nisha joins us from the University of Manchester, having studied the molecular determinants of PARG inhibitor sensitivity for her PhD. Welcome Nisha!
Our latest paper is out!
Our latest paper is out: Fragment-based screening identifies molecules targeting the substrate-binding ankyrin repeat domains of tankyrase. Thank you to our collaborators Ian Collins (ICR) and Mark Pfuhl (King’s College London)! Many congratulations to the whole team, in particular first author Katie Pollock on her PhD work! You can read about the work in this ICR press release.
Team member Yexin Xie attends EMBO Course in Practical Integrative Structural Biology
PhD student Yexin Xie has been awarded a place at the EMBO Course “Practical Integrative Structural Biology”. The course takes place at EMBL Hamburg and the Centre for Structural Systems Biology. Congratulations Yexin!
Pathways to Independence and Dean’s Award to Postdoctoral Fellow Michael Ranes
Postdoctoral Fellow Michael Ranes has been awarded a place at the prestigious Pathways to Independence training programme, a joint initiative by the ICR, Sanger, MRC, and Cancer Research UK institutes and the Babraham Institute. The programme provides training for future scientific leaders. Michael has also received a £5,000 Dean’s Award to develop his independent research programme. Congratulations Michael!
Welcome William and Oviya!
Our lab is growing. We welcome Oviya Inian and William (Billy) Fisher into the lab. Oviya is a Postdoctoral Fellow who joins our telomere team. Billy joins us for a two-month summer project funded by a Lister Institute Summer Studentship.
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