Summer Research Lab Experience

Join one of our research teams

You will be a member of one of our research teams, and your work will be an important contribution to the group’s discoveries. Summer research lab experience is an invaluable opportunity to gain experience in a research group and to get career advice from fellow students and mentors. They are also a great way to meet new people; we are a small, friendly department, located in the heart of London. For summer 2021, we anticipate that in-person lab work will be possible – in the event that COVID-19 restrictions prevent this, a number of the projects offer a remote working alternative. Please explore the projects below.

Eligibility

Opportunities are funded by a number of learned societies. Please check the eligibility criteria for the specific schemes. In order to be eligible for a research bursary from these organisations you must usually be:
• Taking an undergraduate science degree
• Considering research as a career
• Expecting to achieve a First Class or good Upper Second Class degree result (references will be required)
• In the middle years of your degree e.g. your visit will take place in the Summer vacation before the start of the final year of study
• Registered at a UK university for the majority of your degree (for most funding bodies)

Working hours and stipend

Working hours will be 35 hours per week for between 6-8 weeks.
You can expect to receive a stipend of between £180 and 200 per week during your stay if the application for funding is successful. There are also opportunities for unpaid research lab experience.

How to apply

Potential applicants should contact chosen project supervisors by Monday 12 April 2021.
When contacting supervisors please forward:
• A copy of your current CV
• A brief statement of support outlining your interest in the project and your suitability
• The name of an academic referee


Dr. Anaïs Cassaignau (working with Prof. John Christodoulou), Institute of Structural and Molecular Biology at UCL and Birkbeck

Project: Investigation of structure formation during protein biosynthesis on the ribosome using NMR pseudocontact shift measurements
Proteins acquire structure during their synthesis on the ribosome once they emerge from the exit tunnel (see Fig). We study this co-translational folding process by providing high-resolution structural descriptions1 of ribosome-nascent chain complexes (RNCs) via NMR and cryoEM, with the aim to produce experimentally restrained MD simulations2.

The student will participate in our existing NMR approaches to evaluate this highly dynamic process, by complementing existing short-range paramagnetic relaxation enhancement-based distance restraints (15-25Å) with longer restraints covering up to 40Å distances using pseudochemical shift NMR measurements of RNCs.

To this end, the student will utilise our range of Cys-containing variants of Immunoglobulin-RNC constructs2. These RNCs will be produced with selective 15N-labelling as is routinely performed in the group2,3,4 and the Cys-residue will be modified to incorporate DOTA-caged lanthanide tags5 to produce NMR PCS measurements. If time permits the student will initiate the building of an atomic model together with an MD expert in the JC group (Dr Tomasz Wlodarski) using an existing framework with PRE-restraints obtained from NMR measurements.

Should the pandemic prevent practical work, the student will be able to exclusively focus on the computational framework described here using existing data.

[1] Cassaignau, A. M. E., Cabrita, L. D. & Christodoulou, J. How Does the Ribosome Fold the Proteome? Annu. Rev. Biochem. 89, 389–415 (2020).

[2] Cassaignau A.M. et al. A strategy for co-translational folding studies of ribosome-bound nascent chain complexes using NMR spectroscopy. Nat Protoc. 2016 Aug; 11(8): 1492-507.

[3] Cabrita L.D. et al. A structural ensemble of a ribosome-nascent chain complex during cotranslational protein folding. Nature Structural & Molecular Biology. 2016 Feb; 23: 278-85.

[4] Deckert A. et al. Structural characterization of the interaction of alpha-synuclein nascent chains with the ribosomal surface and trigger factor. Proc Natl Acad Sci U S A. 2016 May: 113(18), 5012-17.

[5] Häussinger, D., Huang, J.-R. & Grzesiek, S. DOTA-M8: An Extremely Rigid, High-Affinity Lanthanide Chelating Tag for PCS NMR Spectroscopy. J. Am. Chem. Soc. 131, 14761–14767 (2009).


Prof. Christine Orengo, Research Department of Structural and Molecular Biology, UCL

Project: Finding protein folds and evolutionary relationships
The CATH Classification groups evolutionary related proteins and identifies similarity in their folds because the protein’s 3D-shape determines function. This project will be involved in analysing newly determined proteins to see if they have novel folds. We have a suite of in-house programs that are run to find these structural relationships. Results are presented via webpages to allow multiple data to be inspected. The project will also involve testing machine learning strategies to detect very distantly related proteins as these homologues can bring important new insights into evolutionary processes and suggest novel functions. We are trialling some advanced machine learning strategies that combine a range of structure and sequence features to detect these distant homologues and will explore state-of-the-art approaches.

The project is computational and involves running in-house computational methods and on-line protocols. It also involves visualisation and manual inspection of protein structures. Training will be given in all the methods. We collaborate with the European Bioinformatics Institute (EBI) and some of the new approaches will be considered for uptake in computational platforms being set up together with the EBI for the 3D-SCAfold project. Programming skills are not necessary but would be an advantage.
The summer project would be carried out with remote working. All the programs can easily be run remotely and the group has a dedicated website where the data and results are accessible.


Dr. Ruth Pritchard (working with Prof. Laurence Pearl and Prof. John Christodoulou), Institute of Structural and Molecular Biology at UCL and Birkbeck & University of Sussex

Project: HSP90 chaperoning of the oncogenic BRaf kinase
HSP90 is an essential chaperone involved in stabilising and activating a wide range of proteins including the oncogenic protein BRaf, which is mutated in numerous cancers. Specific recognition of diverse client proteins is mediated by co-chaperones such as cdc37 in the case of BRaf and similar kinases1.

Recent cryoEM structures of the full hsp90:cdc37:kinase complex have shown that the kinase is partially unfolded2 and there is evidence that this unfolding event occurs in the kinase:cdc37 complex, prior to chaperone binding3.

We are using nuclear magnetic resonance (NMR) alongside other biochemical and structural techniques to understand the nature of the BRaf:cdc37 interaction: recognition, specificity and the structural changes that occur on binding. NMR is a particularly powerful tool for this as it can capture changes at atomic level, even if the system is dynamic or disordered.

This project involves designing and expressing a cdc37 mutant, and using NMR to characterise its interaction with BRaf in order to better understand how the kinase and co-chaperone interact prior to the interaction with HSP90.
The project can be adapted for home and would involve developing data processing and analysis workflows to assess the behaviour of existing mutants and placing findings in the context of the wider body of literature. This would use a combination of python and specialist NMR software with an option to extend into computational modelling should the project progress well.

1. Pearl 2005 Curr Opin Genet Dev 15:55
2. Verba et al. 2016 Science 352:1542
3. Keramisanou et al. 2017 Mol Cell 62:260


Prof. Stephen Perkins, Structural Immunology Group; Molecular Interactions Facility, Research Department of Structural and Molecular Biology, UCL
Email: s.perkins@ucl.ac.uk

Project: Interactive databases for genetic variants in the coagulation proteins
The project will address the molecular role of defective plasma proteins in causing disease. We have generated well-received interactive databases that combine genetic variants in specific plasma proteins with disorders such as in haemophilia or in inflammatory disease caused by variants in the complement proteins (see our variants web-site http://www.complement-db.org/home.php). The databases are useful for both clinicians and basic science researchers. Genetic variants in the evolutionarily-related coagulation proteins of haemophilia (excessive bleeding and failure to clot) are involved in Haemophilia A and B, as well as a number of rare types of these disorders. There, we have created databases for the F7, F8, F9 and F11 genes [Ref 1], several of which are being updated at present. The aim of this summer project is to upgrade and update one of our coagulation databases to bring it up-to-date during the 8 weeks of the studentship. The student will perform literature searches and searches of other on-line resources, assemble these in a MySQL database, learn web-site programming, and present the web site on-line. These are transferable skills that are useful in many contexts. As a computational project, this project is relatively unaffected by COVID, and can be done on-campus or off-campus.

References
[1] Rallapalli, P. M., Kemball-Cook, G., Tuddenham, E. G., Gomez, K. & Perkins, S. J. (2013). A new interactive web database of mutations in coagulation factor IX provides novel insights into the phenotypes and genetics of haemophilia B. J. Thromb. Haemost. 11, 1329-1340. Pubmed 23617593. doi: 10.1111/jth.12276
[2] Osborne, A. J., Breno, M., Borsa, N. G., Bu, F., Fremeaux-Bacchi, V., Gale, D. P., van den Heuvel, L. P., Kavanagh, D., Noris, M., Pinto, S., Rallapalli, P. M., Remuzzi, G., Rodriguez de Cordoba, S., Ruiz, A., Smith, R. J. H., Vieira-Martins, P., Volokhina, E., Wilson, V., Goodship, T. H. J. & Perkins, S. J. (2018) Statistical validation of rare complement variants provides insights on the molecular basis of atypical haemolytic uraemic syndrome and C3 glomerulopathy. J. Immunology. 200, 2464-2478. Pubmed 29500241 DOI: https://doi.org/10.4049/jimmunol.1701695

Requirements
If based at UCL, ideally taking BIOC2004 (Protein Structure and Function) and/or IMMU2001 (Immunology). Please provide a brief CV, a supporting statement of why you are interested in the project, the name of an academic referee, and your UCL PORTICO printout (or transcript) when applying.


Dr. Anthony Roberts, Department of Biological Sciences, Birkbeck
Email: a.roberts@mail.cryst.bbk.ac.uk, Website: www.roberts-lab.com

Project: Building the cilium with ATP-driven molecular motors

The goal of this project is to elucidate the mechanisms underlying cilium construction, in particular the role of the ATP-driven transport complexes. Virtually every cell type in the human body builds a cilium: a microtubule-based projection from the plasma membrane. It has emerged that these antennae-like structures are crucial for sensing light, smell, fluid flow, and morphogens. Their dysfunction is associated with a variety of human disorders, including obesity, blindess, kidney disease, and developmental defects.

How the cell builds the cilium – a complex organelle with defined size, architecture, and protein composition – is a major unsolved question. Central to cilium construction are the molecular motors kinesin and dynein. These motor proteins transport building blocks and signaling molecules to and from the cilium tip, using ATP hydrolysis to move along ciliary microtubules.

Elucidating the structure and mechanism of the ciliary motor protein complexes has been challenging, in part because they are formed by large subunits that fail to fold correctly when expressed in bacteria. In this project you will exploit eukaryotic protein expression systems [1] to produce and analyze protein constructs and thereby investigate how the motors move and are regulated. In addition to molecular biology and biochemistry, you will gain exposure to cryo electron microscopy and single-molecule fluorescence microscopy, providing insight into the structure and dynamics of this molecular machinery. In the event laboratory working is not possible due to COVID restrictions, this project is also well suited for in silico structural analysis.

Building the cilium with ATP-driven molecular motors. (A) Depiction of the cilium, its microtubule doublets and IFT trains propelled by kinesin and dynein. (B) The cryo-EM structure of the 1.4 MDa dynein-2 complex, recently solved in the group1, which raises a number of mechanistic questions.

References

  1. Toropova K, Zalyte R, Mukhopadhyay AG, Mladenov M, Carter AP, Roberts AJ. (2019) Structure of the dynein-2 complex and its assembly with intraflagellar transport trains. Nature Structural & Molecular Biology 26(9):823-829.

Dr. Giulia Zanetti, Department of Biological Sciences, Birkbeck

In the Zanetti lab, we are interested in understanding the molecular mechanisms of COPII membrane budding and its regulations.
We take a bottom-up approach by reconstituting COPII budding in vitro from artificial membranes, and analysing the formed coated vesicles by cryo-electron microscopy (Hutchings et al., 2018, 2020).
We have recently prepared membranes that contain cargo proteins and reconstituted budding. By the summer, we will have a structure of the cargo-bound coat that will reveal the molecular details of the interactions between cargo and coat in the context of a membrane.
The summer student will use this structure to design, clone and purify mutants aimed at disrupting the coat-cargo interaction. They will then perform in vitro reconstitutions and shadow current postdocs with negative-stain electron microscopy. Visualisation of the coated membranes and comparison of the results in the wild type versus mutant scenario will give insights into the structural role of cargo binding in coat assembly and architecture.
With this project, the student will gain experience with molecular biology, protein biochemistry, membrane work and electron microscopy.

Alternative home-bound project:
We are constantly developing and optimising protocols for cryo-tomographic data processing. The student will be able to participate in our effort to streamline automatic tomogram reconstructions. This will provide experience with coding and matlab, as well as giving a good understanding of the theory of electron microscopy and image processing.