Integrative Structural Biology of Cell Division and Energy Homeostasis
Department for Molecular Biology, University of Geneva, Boland lab, Switzerland
Lab profile
Our Structures
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Welcome to the Boland lab! We are a small, focused and enthusiastic group working at the intersection of Structural Biology, Molecular Biology and Cell Biology. We leverage the latest developments in Structural Biology, and here in particular cryo-electron microscopy (cryo-EM) with complementary biophysical techniques (proteomics, light-microscopy, microfluidics, etc.), to adress complex biological questions in the field of cell cycle regulation and cell signaling.
News
- The first paper of the lab is out now in Nature.
Research interests |
Structural basis of cell division and energy metabolism
In recent years, cryo-electron microscopy has been proven to be an extremely powerful tool to obtain unprecedented high-resolution information of particular challenging protein targets, such as large macro-molecular machines or membrane proteins, many of which seemed inaccessible to structural studies only a few years ago. Technological advances including commercially available direct electron detector (DED) in combination with the development of new computational algorithms have revolutionized the field of cryo-electron microscopy and structural biology in general. Recently published structures of putative pharmaceutical targets have emphasized the potential of cryo-electron microscopy for structure-based drug design.
Structural basis of cell cycle regulation
Cell division is studied for both, its beauty and for the danger that comes with it. When all goes well, a new healthy cell emerges. Aberrant cell division, however, causes the transformation of normal growing cells into cancer cells. To maintain genome stability during cell division, each emerging daughter cell needs to receive an identical set of sister chromatids. This requires precision during two key processes: DNA replication in S phase and segregation of sister chromatids during mitosis (M phase).
In early mitosis, the duplicated chromosomes are held together by the ring-shaped cohesin complex. Separation of chromosomes during anaphase is triggered by separase-a large cysteine endopeptidase that cleaves the cohesin subunit SCC1 (also known as RAD21). Separase is activated by degradation of its inhibitors, securin and cyclin B, but the molecular mechanisms of separase regulation are not clear. We show that both, securin and the Cdk1-cyclin B1-Cks1 complex, inhibit separase by pseudosubstrate motifs that block substrate binding at the catalytic site and at nearby docking sites. As in Caenorhabditis elegans (Boland et al., NSMB, 2017) and yeast, human securin contains its own pseudosubstrate motifs. By contrast, CDK1-cyclin B1 inhibits separase by deploying pseudosubstrate motifs from intrinsically disordered loops in separase itself. One autoinhibitory loop is oriented by CDK1-cyclin B1 to block the catalytic sites of both separase and CDK1. Another autoinhibitory loop blocks substrate docking in a cleft adjacent to the separase catalytic site. A third separase loop contains a phosphoserine that promotes complex assembly by binding to a conserved phosphate-binding pocket in cyclin B1. Our study reveals the diverse array of mechanisms by which securin and CDK1-cyclin B1 bind and inhibit separase, providing the molecular basis for the robust control of chromosome segregation.
Fig. 1 Auto-inhibitory loops in separase
Fig. 2 Cdk1 inhibition by a pseudo substrate sequence located in separase. Complex formation of separase-CCC renders CDK1 and separase inactive
Fig.3 A phosphate-binding pocket in B-type cyclins (left)
News & Views
Understanding the molecular basis of metabolic protein clusters
Enzymes frequently cluster into large higher-order structures, also termed “metabolons”, to execute sequential, multistep cascade reactions. These macromolecular complexes provide several metabolic advantages, such as substrates channelling between catalytic sites, higher flux rates that are important if the substrate intermediates are instable (i.e. short half-life) and they ensure a high overall catalytic efficiency.
We are using state-of-the-art microscopy methods, such as single particle analysis (SPA), correlative light and electron microscopy (CLEM) combined with FIB-SEM and time-resolved electron microscopy (TREM) to characterise the structure & architecture of such large complex assemblies. We will visualise conformational changes upon substrate binding and determine the underlying kinetics using classical biochemical and biophysical methods. The figure on the right shows the overall architecture of one of our target complexes (negative stain microscopy; top) and the spraying device that will be used to conduct TREM studies (bottom).
Our negative stain reconstruction of a metabolon
Spraying device to perform TrEM experiments
Cytokine-mediated cell signaling
Cytokines are small soluble proteins that facilitate communication between cells in the immune and hematopoietic system. In response to external stimuli, they bind to specific cell surface receptors to trigger intracellular signalling cascades that are vital for a broad spectrum of cell functions, including proliferation and differentiation, immune responses and energy metabolism. Consequently, cytokines and their receptors are highly relevant drug targets. To elucidate the structure-function relationship of selected target receptors will be the second main branch of our lab research.
Schematic drawing of cytokine receptor embedded in a lipid bilayer
People
Andreas Boland, PhD
Assistant Professor at the University of Geneva
(Department of Molecular Biology)
+41 22 379 61 27
Marie Skłodowska-Curie Alumni, EMBO Alumni
https://orcid.org/0000-0003-1218-6714
https://publons.com/researcher/2717206/andreas-boland/
https://scholar.google.co.uk/citations?user=6Vvsl-cAAAAJ&hl=en&oi=sra
Research specialists
Postdoctoral researcher
PhD candidates
Publications
* equal contribution
# corresponding author
bold Boland group member
2021
Deciphering the modes of human separase inhibition by securin and CDK1-CCNB1
Raia P, Yu J, Boland A#.
Molecular & Cellular Oncology. 2021 September; 596
Structural basis of human separase regulation by securin and CDK1-cyclin B1
Yu J, Raia P, Ghent CM, Raisch T, Sadian Y, Cavadini S, Sabale PM, Barford D, Raunser S, Morgan DO, Boland A#.
Nature. 2021 July; 596, 138–142
Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embrace
Heimhalt M, Berndt A, Wagstaff J, Perisic O, Maslen S, Yu C W-H, Anandapadamanaban M, Masson GR, Boland A, Ni X, Yamashita K, Murshudov GN, Skehel M, Freund SM, Williams RL.
eLife. 2021 September 14; 10:e68799
2020
Structure of the DOCK2-ELMO1 Complex Provides Insights Into Regulation of the Auto-Inhibited State
Chang L, Yang J, Jo CH, Boland A, Zhang Z, McLaughlin SH, Abu-Thuraia A, Killoran RC, Smith MJ, Côté J-F, Barford D.
Nature Communications. 2020 July 10;11(1):3464.
2019
A tri-ionic anchor mechanism drives Ube2N-specific recruitment and K63-chain ubiquitination in TRIM ligases.
Kiss L, Zeng J, Dickson CF, Mallery DL, Yang JC, McLaughlin SH, Boland A, Neuhaus D, James LC.
Nature Communications. 2019 October 3;10(1):4502.
2018
The CryoEM Structure of the Ribosome Maturation Factor Rea1.
Sosnowski P, Urnavicius L, Boland A, Fagiewicz R, Busselez J, Papai G, Schmidt H.
eLife. 2018 November 21;7 epub.
2017
The potential of cryo-electron microscopy for structure-based drug design.
Boland A, Chang L, Barford D.
Essays in Biochemistry. 2017 November;61(5):543-560
Cryo-EM structure of a metazoan separase-securin complex at near-atomic resolution.
Boland A#, Martin TG, Zhang Z, Yang J, Bai X-C, Chang L, Scheres S, Barford D.
Nat Struct Mol Biol. 2017 April;24(4):414-418
2015
Fast native-SAD phasing for routine macromolecular structure determination.
Weinert T, Olieric V, Waltersperger S, Panepucci E, Chen L, Zhang H, Zhou D, Rose J, Ebihara A, Kuramitsu S, Li D, Howe N, Pautsch A, Bargsten K, Prota A, Surana P, Kottur J, Nair D, Basilico F, Cecatiello V, Pasqualato S,
Boland A, Weichenrieder O, Dekker C, Wang B-C, Steinmetz M, Caffrey M, Wang M.
Nature methods. 2015 Feb;12(2):131-133
2014
A DDX6-CNOT1 complex and W-binding pockets in CNOT9 reveal direct links between
miRNA target recognition and silencing.
Chen Y*, Boland A*, Kuzuoğlu-Öztürk D*, Bawankar P, Chang CT, Loh B, Weichenrieder O,
Izaurralde E.
Mol Cell. 2014, Jun 5;54(5):737-50, *equal contributions
2013
Structure and assembly of the NOT module of the CCR4-NOT complex.
Boland A*, Chen Y*, Raisch T*, Jonas S*, Kuzuoğlu-ÖztürkD, Wohlbold L, Weichenrieder O, Izaurralde E.
Nat Struct Mol Biol. 2013 Nov;20(11):1289-97, *equal contributions
Structure of the PAN3 pseudokinase reveals the basis for interactions with the PAN2 deadenylase and the GW182/TNRC6 proteins.
Christie M*, Boland A*, Huntzinger E, Weichenrieder O, Izaurralde E.
Mol Cell. 2013 Aug 8;51(3):360-73,*equal contributions
2012
A direct interaction between DCP1 and XRN1 couples mRNA decapping to 5' exonucleolytic degradation.
Braun JE, Truffault V, Boland A, Huntzinger E, Chang CT, Haas G, Weichenrieder O,
Coles M,Izaurralde E.
Nat Struct Mol Biol. 2012
2011
Crystal structure of the MID-PIWI lobe of a eukaryotic Argonaute protein.
Boland A, Huntzinger E, Schmidt S, Izaurralde E, Weichenrieder O.
Proc Natl Acad Sci U S A. 2011
2010
Crystal structure and ligand binding of the MID domain of a eukaryotic Argonaute protein.
Boland A, Tritschler F, Heimstädt S, Izaurralde E, Weichenrieder O.
EMBO Rep.2010
Facilities
The University of Geneva offers a vast range of outstanding scientific facilities and support services, all available to members of the lab.
Members have acces to the electron microscopy facility which includes a FEI Tecnai™ G2 Sphera for cryo-EM single particle analysis and a JEOL JSM-6510LV scanning electron microscope.
In the near future this facility will be upgraded by two more electron microscopes, including a Talos L120C (an ideal screening microscope for single particle analysis), as well as a state-of-the-art Talos Arctica microscope equipped with a Falcon III detector enabling high-resolution data collection (see images on the right).
More information can be found on the Bioimaging Center website of the University (http://bioimaging.unige.ch/).
The Bioimaging Center was founded in 2002 by the NCCR Frontiers in Genetics. It is a common platform of the Faculty of Sciences and iGE3. Under the auspices of the iGE3, it is mainly supported by the Section of Biology and the Biochemistry Department. The Center is open to the entire scientific and biomedical community of the Geneva academic landscape.
It is dedicated to providing state-of-the-art equipment and technology for light and electron microscopy. Specialists offer advice and guidance for each step of your imaging project starting from experimental approach to data analysis.
Yashar Sadian
- EM specialist
Christoph Bauer
- Managing Director
FEI Talos Arctica
Talos L120C
FEI Tecnai G2 Sphera
Funding - Special thanks to all our current funding bodies
Past Funding
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Marie Skłodowska-Curie postdoctoral fellowship. Horizon 2020 programme, (2016-2018)
-
EMBO Long-Term Fellowship, 2014-2016
-
Career developmental fellowship (CDF) by the MRC-LMB (2014)
-
Predoctoral Fellowship by the International Max Planck Research School, (2009-2013)
Contact Us
Mailing adress:
Boland laboratories
Department of Molecular Biology, Sciences III
30 Quai E. Ansermet
1211 Geneva, Switzerland
Lab: (858) 784-8761
Fax: (858) 784-9985
CONTACT US
last modified August 2021