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CilDyn SIGNED

Molecular analysis of the Hedgehog signal transduction complex in the primary cilium

Total Cost €

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EC-Contrib. €

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Partnership

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 CilDyn project word cloud

Explore the words cloud of the CilDyn project. It provides you a very rough idea of what is the project "CilDyn" about.

plasma    signal    entire    orchestrating    hedgehog    relies    ray    antenna    vertebrate    atomic    cilium    fulfil    understand    transport    live    compartment    emphasis    accumulation    organisation    temporal    microtubule    proteins    multivalent    complexes    rules    function    techniques    me    enriched    functions    dynamically    almost    functional    protrudes    biological    membrane    connection    discoveries    localised    upstream    interfaces    molecular    transduction    therapy    signalling    time    cancer    fluorescence    laboratory    dynamic    therapeutics    direct    decade    primary    human    ultimate    last    reagents    combines    components    size    crystallography    fundamental    unexpected    localisation    linked    insights    deciphering    questions    spatial    feed    consolidate    imaging    protein    anti    micro    architecture    transcription    transmembrane    regulation    morphogen    stem    receptor    binary    structural    developmental    transducer    class    combine    assembly    potentially    world    microscopy    interactions    hh    biology    cell    cascade   

Project "CilDyn" data sheet

The following table provides information about the project.

Coordinator
THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD 

Organization address
address: WELLINGTON SQUARE UNIVERSITY OFFICES
city: OXFORD
postcode: OX1 2JD
website: www.ox.ac.uk

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country United Kingdom [UK]
 Project website https://www.strubi.ox.ac.uk/research/christian-siebold
 Total cost 1˙727˙456 €
 EC max contribution 1˙727˙456 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2014-CoG
 Funding Scheme ERC-COG
 Starting year 2015
 Duration (year-month-day) from 2015-08-01   to  2020-07-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD UK (OXFORD) coordinator 1˙727˙456.00

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 Project objective

The unexpected connection between the primary cilium and cell-to-cell signalling is one of the most exciting discoveries in cell and developmental biology in the last decade. In particular, the Hedgehog (Hh) pathway relies on the primary cilium to fulfil its fundamental functions in orchestrating vertebrate development. This microtubule-based antenna, up to 5 µm long, protrudes from the plasma membrane of almost every human cell and is the essential compartment for the entire Hh signalling cascade. All its molecular components, from the most upstream transmembrane Hh receptor down to the ultimate transcription factors, are dynamically localised and enriched in the primary cilium. The aim of this proposal, which combines structural biology and live cell imaging, is to understand the function and signalling consequences of the multivalent interactions between Hh signal transducer proteins as well as their spatial and temporal regulation in the primary cilium. The key questions my laboratory will address are: What are the rules for assembly of Hh signal transduction complexes? How dynamic are these complexes in size and organisation? How are these processes linked to the transport and accumulation in the primary cilium?

I will combine state-of-the art structural biology techniques (with an emphasis on X-ray crystallography) to study the molecular architecture of binary and higher-order Hh signal transduction complexes and live cell fluorescence microscopy (for protein localisation and direct protein interactions). These two approaches will allow me to identify and define specific protein-protein interfaces at the atomic level and test their functional consequences in the cell in real time. My goal is to consolidate a world-class morphogen signal transduction laboratory, deciphering fundamental biological insights. Importantly, my results and reagents can potentially feed into the development of novel anti-cancer therapeutics and reagents promoting stem cell therapy.

 Publications

year authors and title journal last update
List of publications.
2019 Maia Kinnebrew, Ellen J Iverson, Bhaven B Patel, Ganesh V Pusapati, Jennifer H Kong, Kristen A Johnson, Giovanni Luchetti, Kaitlyn M Eckert, Jeffrey G McDonald, Douglas F Covey, Christian Siebold, Arun Radhakrishnan, Rajat Rohatgi
Cholesterol accessibility at the ciliary membrane controls hedgehog signaling
published pages: , ISSN: 2050-084X, DOI: 10.7554/elife.50051
eLife 8 2020-03-13
2019 Amalie F. Rudolf, Maia Kinnebrew, Christiane Kowatsch, T. Bertie Ansell, Kamel El Omari, Benjamin Bishop, Els Pardon, Rebekka A. Schwab, Tomas Malinauskas, Mingxing Qian, Ramona Duman, Douglas F. Covey, Jan Steyaert, Armin Wagner, Mark S. P. Sansom, Rajat Rohatgi, Christian Siebold
The morphogen Sonic hedgehog inhibits its receptor Patched by a pincer grasp mechanism
published pages: 975-982, ISSN: 1552-4450, DOI: 10.1038/s41589-019-0370-y
Nature Chemical Biology 15/10 2020-03-13
2019 Thomas Lanyon-Hogg, Markus Ritzefeld, Lea Sefer, Jasmine K. Bickel, Amalie F. Rudolf, Nattawadee Panyain, Ganka Bineva-Todd, Cory A. Ocasio, Nicola O\'Reilly, Christian Siebold, Anthony I. Magee, Edward W. Tate
Acylation-coupled lipophilic induction of polarisation (Acyl-cLIP): a universal assay for lipid transferase and hydrolase enzymes
published pages: 8995-9000, ISSN: 2041-6520, DOI: 10.1039/c9sc01785b
Chemical Science 10/39 2020-03-13
2019 Jennifer H. Kong, Christian Siebold, Rajat Rohatgi
Biochemical mechanisms of vertebrate hedgehog signaling
published pages: dev166892, ISSN: 0950-1991, DOI: 10.1242/dev.166892
Development 146/10 2020-03-13
2019 Christiane Kowatsch, Rachel E Woolley, Maia Kinnebrew, Rajat Rohatgi, Christian Siebold
Structures of vertebrate Patched and Smoothened reveal intimate links between cholesterol and Hedgehog signalling
published pages: 204-214, ISSN: 0959-440X, DOI: 10.1016/j.sbi.2019.05.015
Current Opinion in Structural Biology 57 2020-03-13
2019 Rory Nolan, Maro Iliopoulou, Christian Siebold, E. Yvonne Jones, Sergi Padilla-Parra
Robin Hood: non-fitting, non-smoothing image detrending for bleaching correction
published pages: , ISSN: , DOI: 10.1101/667824
bioRxiv 667824 2020-03-13
2019 Daniel Rozbesky, Ross A. Robinson, Vitul Jain, Max Renner, Tomas Malinauskas, Karl Harlos, Christian Siebold, E. Yvonne Jones
Diversity of oligomerization in Drosophila semaphorins suggests a mechanism of functional fine-tuning
published pages: , ISSN: 2041-1723, DOI: 10.1038/s41467-019-11683-y
Nature Communications 10/1 2020-03-13
2019 George Hedger, Heidi Koldsø, Matthieu Chavent, Christian Siebold, Rajat Rohatgi, Mark S.P. Sansom
Cholesterol Interaction Sites on the Transmembrane Domain of the Hedgehog Signal Transducer and Class F G Protein-Coupled Receptor Smoothened
published pages: 549-559.e2, ISSN: 0969-2126, DOI: 10.1016/j.str.2018.11.003
Structure 27/3 2020-03-13
2018 Rory Nolan, Luis A. Alvarez, Samuel C. Griffiths, Jonathan Elegheert, Christian Siebold, Sergi Padilla-Parra
Calibration-free In Vitro Quantification of Protein Homo-oligomerization Using Commercial Instrumentation and Free, Open Source Brightness Analysis Software
published pages: , ISSN: 1940-087X, DOI: 10.3791/58157
Journal of Visualized Experiments 137 2019-05-31
2017 Christian Siebold, Toshihide Yamashita, Philippe P. Monnier, Bernhard K. Mueller, R. Jeroen Pasterkamp
RGMs: Structural Insights, Molecular Regulation, and Downstream Signaling
published pages: 365-378, ISSN: 0962-8924, DOI: 10.1016/j.tcb.2016.11.009
Trends in Cell Biology 27/5 2019-05-31
2016 Eamon F. X. Byrne, Ria Sircar, Paul S. Miller, George Hedger, Giovanni Luchetti, Sigrid Nachtergaele, Mark D. Tully, Laurel Mydock-McGrane, Douglas F. Covey, Robert P. Rambo, Mark S. P. Sansom, Simon Newstead, Rajat Rohatgi, Christian Siebold
Structural basis of Smoothened regulation by its extracellular domains
published pages: 517-522, ISSN: 0028-0836, DOI: 10.1038/nature18934
Nature 535/7613 2019-05-31
2018 Eamon FX Byrne, Giovanni Luchetti, Rajat Rohatgi, Christian Siebold
Multiple ligand binding sites regulate the Hedgehog signal transducer Smoothened in vertebrates
published pages: 81-88, ISSN: 0955-0674, DOI: 10.1016/j.ceb.2017.10.004
Current Opinion in Cell Biology 51 2019-05-31
2018 David R. Raleigh, Navdar Sever, Pervinder K. Choksi, Monika Abedin Sigg, Kelly M. Hines, Bonne M. Thompson, Daniel Elnatan, Priyadarshini Jaishankar, Paola Bisignano, Francesc R. Garcia-Gonzalo, Alexis Leigh Krup, Markus Eberl, Eamon F.X. Byrne, Christian Siebold, Sunny Y. Wong, Adam R. Renslo, Michael Grabe, Jeffrey G. McDonald, Libin Xu, Philip A. Beachy, Jeremy F. Reiter
Cilia-Associated Oxysterols Activate Smoothened
published pages: 316-327.e5, ISSN: 1097-2765, DOI: 10.1016/j.molcel.2018.08.034
Molecular Cell 72/2 2019-04-18
2018 Jonathan Elegheert, Ester Behiels, Benjamin Bishop, Suzanne Scott, Rachel E. Woolley, Samuel C. Griffiths, Eamon F. X. Byrne, Veronica T. Chang, David I. Stuart, E. Yvonne Jones, Christian Siebold, A. Radu Aricescu
Lentiviral transduction of mammalian cells for fast, scalable and high-level production of soluble and membrane proteins
published pages: 2991-3017, ISSN: 1754-2189, DOI: 10.1038/s41596-018-0075-9
Nature Protocols 13/12 2019-04-18

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