Structural cell biology

Lead Research Organisation: MRC Laboratory of Molecular Biology

Abstract

A combination of structural, cellular and molecular methods will be used to define the molecular mechanisms that underlie key processes in cellular biology. This project will look at the ways molecules such as proteins and nucleic acids are exchanged between the nucleus and the cytoplasm of cells through nuclear pores. These exchanges are important for controlling cell function and are mediated by specific carrier molecules. Understanding how nuclear transport works, especially in the context of molecules that have the potential to be useful in understanding cancer development, may aid in the development of therapies.

Technical Summary

I propose to use structural methods to establish the interaction interfaces between molecules that are important to nucleocytoplasmic transport and its integration with other nuclear components of the gene expression machinery and use this information to engineer mutants that can be used to define the functional contribution of each interaction. In nuclear transport, the exchange of cargo macromolecules, such as proteins and mRNA, between the nuclear and cytoplasmic compartments through nuclear pores is mediated by specific carrier molecules. My previous work on nuclear pore proteins (FG nucleoporins) will be extended to address precisely how they contribute to translocation through nuclear pores and serve as scaffolds to facilitate the assembly/disassembly of cargo:carrier complexes and recycling of carriers. The nuclear transport components of major nuclear export pathways, especially those involving mRNA, will also be investigated, with emphasis on the molecular mechanism by which export-competent mRNA complexes are generated in the nucleus and disassembled in the cytoplasm. In addition, previous studies on mRNA export and FG-nucleoporins will be extended to encompass the interactions between different components of the gene expression machinery, especially those that are co-ordinated by scaffolds based on nucleoporins or mRNA export components. The role of nuclear pore proteins in gene gating - the tethering of active genes to nuclear pores - will also be explored, especially in the context of complexes involving Sac3 (GANP in humans). The application of the work on nuclear transport to prostate cancer is being explored in collaboration with Prof David Neal, University of Cambridge.

Publications

10 25 50

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Aibara S (2015) Structural characterization of the principal mRNA-export factor Mex67-Mtr2 from Chaetomium thermophilum. in Acta crystallographica. Section F, Structural biology communications

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Christie M (2016) Structural Biology and Regulation of Protein Import into the Nucleus. in Journal of molecular biology

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Conti E (2006) Karyopherin flexibility in nucleocytoplasmic transport. in Current opinion in structural biology

 
Description EC Marie Curie Fellowship
Amount £154,876 (GBP)
Organisation Marie Sklodowska-Curie Actions 
Sector Charity/Non Profit
Country Global
Start 06/2007 
End 06/2010
 
Description EMBO Fellowship
Amount £25,000 (GBP)
Organisation European Molecular Biology Organisation 
Sector Charity/Non Profit
Country Germany
Start 06/2010 
End 06/2011
 
Description MRC Studentship
Amount £14,900 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2011 
End 12/2014
 
Description Merit Award (R37)
Amount £174,760 (GBP)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 06/2006 
End 12/2012
 
Description Wellcome Trust Programme Grant (Structural and functional analysis of interactions involving the nuclear transport machinery that generate nuclear RNA and protein export and orchestrate mitotic spindle assembly)
Amount £535,853 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2006 
End 10/2011
 
Description cell motility 
Organisation Florida State University
Country United States 
Sector Academic/University 
PI Contribution Structural biology of cell motility of amoeboid nematode sperm
Collaborator Contribution enabled collaboration involving nematode sperm
Impact understanding of the fundamental mechanism by which locomotion is generated (see publications). Multidisciplinary involving structural biology, condensed matter physics, structural biology and biochemistry.
 
Description gene gating 
Organisation Heidelberg University
Country Germany 
Sector Academic/University 
PI Contribution structure of complexes involved in gene gating
Collaborator Contribution complemented structural work with yeast geneticsunderstanding the role of GANP in nuclear portein export and gene gating
Impact structure-function relationships in gene gating Interdisciplinary involving structural biology, biochemistry and cell biology
Start Year 2006
 
Description gene gating 
Organisation Medical Research Council (MRC)
Department MRC Cancer Cell Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution structure of complexes involved in gene gating
Collaborator Contribution complemented structural work with yeast geneticsunderstanding the role of GANP in nuclear portein export and gene gating
Impact structure-function relationships in gene gating Interdisciplinary involving structural biology, biochemistry and cell biology
Start Year 2006
 
Description nuclear trafficking 
Organisation Emory University
Country United States 
Sector Academic/University 
PI Contribution Structure and function of key components of nuclear trafficking pathways
Collaborator Contribution Enabled yeast genetics to be employed to complement structural work done in Cambridge
Impact Structure-function relationships in nuclear trafficking - see publications MUltidisciplinary involving structural biology, cell biology and biochemistry
 
Description nuclear transport proteins 
Organisation University of Queensland
Country Australia 
Sector Academic/University 
PI Contribution theory of conformation changes in nuclear transport proteins
Collaborator Contribution Complemented theoretic studies done in Cambridge
Impact understanding of the role of protein flexibility in transport complex formation and disassembly Interdisciplinary involving structural biology, computational biology and cell biology
 
Description EMBO Plenary Lecture at international SCANZ Crystal7 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact EMBO plenary speaker at SCANZ Crystallography Meeting, Bunker Bay, WA, Australia. Presented keynote lecture on the structure and function of components of the mRNA nuclear transport system.
Year(s) Of Engagement Activity 2018
 
Description Invited seminar at CalTech 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited seminar at California Institute of Technology, Pasadena, USA
Year(s) Of Engagement Activity 2017
 
Description Invited seminar at University of Queensland 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Seminar on professional development for graduate students
Year(s) Of Engagement Activity 2018
 
Description Invited seminar at University of Sydney 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited seminar regarding career development for graduate students
Year(s) Of Engagement Activity 2018
 
Description Series of lectures and seminars as part of an international crystallography course for graduate students at University of Queensland 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Series of lectures and workshops in international crystallography course
Year(s) Of Engagement Activity 2019
 
Description lab experience 
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 visits of school children to laboratory

inspired students to undertake careers in science
Year(s) Of Engagement Activity 2006,2007,2008,2009