Protein-protein interactions in intracellular signalling

Lead Research Organisation: MRC National Inst for Medical Research

Abstract

To defend ourselves against infection by pathogens our body uses sophisticated mechanisms to detect the presence of pathogens and mount an immune response. It is of fundamental importance that this response occurs in a spatially and timely correct manner as otherwise there is the risk of damage to the host. In fact, improper regulation of immune responses can lead to chronic inflammation and auto-immune diseases and has been linked to cancer. We employ structural and biochemical methods to investigate and describe the three dimensional structure and associated function of proteins that regulate immune responses. The knowledge of such fundamental properties of proteins can help to better understand the cause of disease and might also help to find new drugs against inflammatory disorders and auto-immune disease.|

Technical Summary

Innate immunity relies on the ability to rapidly detect and eliminate pathogens. This is achieved with the help of pattern recognition receptors (PRRs) that recognise evolutionary conserved patterns specific to a large number of pathogens and initiate a pro-inflammatory response. The pathways transducing these signals need to be tightly controlled to avoid chronic inflammation and auto-immune disease. There is close synergistic interplay between innate and adaptive immunity and the two systems are linked through complex signalling networks. ||Our research is focused on the structural and mechanistic characterisation of protein complexes that regulate signalling in innate and adaptive immunity. We are currently studying members of the NLR (NOD-like receptor) family of intracellular pattern recognition receptors. NLRs respond to the presence of bacteria and endogenous danger signals by triggering the activation of the transcription factor NF-kB and production of pro-inflammatory cytokines. In parallel, we are investigating the role of the IKK complex in the activation of NF-kB, a key regulatory complex on which many immune signalling pathways converge. ||Ubiquitination is a key regulatory signal in immune and inflammatory signalling pathways and we are interested in understanding the molecular details of how this post-translational modification is used to transduce a specific signal.

Publications

10 25 50
 
Description Crick-GSK Joint Steering Committee
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description Boehringer Ingelheim Fonds Phd Fellowships
Amount € 67,500 (EUR)
Organisation Boehringer Ingelheim 
Department Boehringer Ingelheim Fonds
Sector Charity/Non Profit
Country Germany
Start 03/2014 
End 09/2016
 
Description Wellcome Trust Grant
Amount £189,325 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2011 
End 09/2014
 
Description DDU Dundee 
Organisation University of Dundee
Department Drug Discovery Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution We have solved the crystal structure of the minimal catalytic fragment of the E3 ubiquitin ligase LUBAC. In addition, we have developed a fluorescence-based assay to follow the catalytic activity of LUBAC. This assay was planned to be used for a high throughput screen of a compound selection owned by the DDU to identify small molecule inhibitors of LUBAC.
Collaborator Contribution The DDU owns the compound library to be screend and will carry out the actrual screen. Should promising small molecules be identified in this screen they will provide medicinal chemistry expertise to further develop the small molecules.
Impact No outputs yet as the original screen was not suitable for a high throughut format and a new screen needed to be developed.
Start Year 2014
 
Description Ikeda, collaboration on LUBAC 
Organisation Austrian Academy of Sciences
Department Institute of Molecular Biotechnology
Country Austria 
Sector Academic/University 
PI Contribution Contributed biochemical expertise and experiments to a joint study on LUBAC
Collaborator Contribution Main contributer to this stdy. Expertise in cell biology and in vivo models of LUBAC and drosophila LUBEL
Impact Joint publications - see publication list for details 1) EMBO Rep. 2016 Nov;17(11):1624-1640. PMID:27702987 2) a joint commissioned reviewed by Dr. Ikeda and myself is currently under review.
Start Year 2015
 
Description Klevit, Collaboration on RBR ligases 
Organisation University of Washington
Department School of Medicine
Country United States 
Sector Academic/University 
PI Contribution Contributed biochemical experiments and expertise on RBR ligases
Collaborator Contribution Main contributer to the joint studies, contributed NMR and biochemical experiments
Impact Joint publications - see publication list for details 1) EMBO Rep. 2016 Aug;17(8):1221-35. doi: 10.15252/embr.201642641. PMID: 27312108 2) another joint manuscript currently under revision at Structure
Start Year 2015
 
Description TRIM family ligases and bacterial pathogens 
Organisation Imperial College School of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Structural and biochemical studies
Collaborator Contribution Cell-based studies
Impact Joint publication: Structural basis for the glycosyltransferase activity of the Salmonella effector SseK3. Esposito D, Günster RA, Martino L, El Omari K, Wagner A, Thurston TLM, Rittinger K. J Biol Chem. 2018 Feb 15. pii: jbc.RA118.001796. doi: 10.1074/jbc.RA118.001796. [Epub ahead of print] PMID: 29449376
Start Year 2016
 
Description Walczak, collaboration on LUBAC 
Organisation University College London
Department UCL Cancer Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration on the characterization of LUBAC. My group contributed bochemical and structural expertise and experiments.
Collaborator Contribution Collaboration on the characterization of LUBAC. The partners are experts in the cell biology and in vivo studies of LUBAC
Impact Two publications have resulted so far from the collaboration - see relevant section for details. 1) Cell Rep. 2015 Dec 15;13(10):2258-72. doi: 10.1016/j.celrep.2015.11.009. PMID:26670046 2) Cell Rep. 2016 Aug 30;16(9):2271-80. doi: 10.1016/j.celrep.2016.07.086. PMID:27545878
Start Year 2015
 
Description A-level student mentoring 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact A scheme set up between the NIMR and the Queen Elizabeth's school in Barnet in which postdocs from the NIMR mentor A-level students for a year. Two postdocs from my group are part of this ongoing activity
Year(s) Of Engagement Activity 2013
 
Description Science basking 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Science busking activity within the context of the MRC Centenary celebrations. One of my postdocs took part in this event.
Year(s) Of Engagement Activity 2013
 
Description Stand/workshop at the Big Bang Science Fair 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Schools
Results and Impact Workshop on the role of DNA

It sparked lively discussions with the pupils
Year(s) Of Engagement Activity 2011
 
Description Wikipedia edit-a-thons 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact MRC Women in Science Wikipedia edit-a-thon on Thursday 25th July. One of my postdocs took part in this event.

Raise awareness of women in science
Year(s) Of Engagement Activity 2013
 
Description Work experience programme 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact My group looked after a work experience student from a local school for a week and allowed her to gain insight into scientific research and made her aware of the possibilities of a degree in a STEM subject.
Year(s) Of Engagement Activity 2017
 
Description Work experince programme 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact My group looked after a work experience student from a local school for a week and allowed her to gain insight into scientific research and made her aware of the possibilities of a degree in a STEM subject.
Year(s) Of Engagement Activity 2018