Postdoctoral opportunities

A consortium including LISCB has been awarded major funding from the EU Marie Skłodowska-Curie (MSCA) COFUND scheme for a project entitled Advanced Multiscale Biological imaging using European Research infrastructures (AMBER). AMBER will fund a five-year postdoctoral programme for 47 postdoctoral researchers to address key needs for biological imaging of fundamental importance to human health.

The consortium has six core partners:

• Lund University/MAX IV
• European Spallation Source, Sweden
• The European Molecular Biology Laboratory
• Institut Laue-Langevin, France
• The International Institute of Molecular Mechanisms and Machines, Poland
• Leicester Institute of Structural and Chemical Biology, United Kingdom.

The first call for postdocs will be advertised imminently. Two positions based in Leicester will be available, with a choice of multiple projects: 

Unravelling the mechanism by which haem modulates the activity of transcription factors

Project leads: Hanna Kwon, Peter Moody and Andrew Hudson

It is becoming clear that the cell biology of haem is wider than its role as a prosthetic group in housekeeping proteins. Haem might not always be inextricably linked to a host, or pivotal to a protein’s functional activity. One example is its ability to modulate the behaviour of transcription factors, such as those that generate the internal-timekeeping system of the mammalian-molecular clock. This type of haem-protein interaction must be transient and reversible, in contrast to the tight binding of a prosthetic group. Whilst certain sequences of amino acids have been implicated as haem-recognition motifs, there is still uncertainty about how haem binds to transcription factors. The reversible nature of the interaction suggests that the binding sites must be altogether different to the binding pockets in haemoproteins. The binding of haem to the transcription factor can be expected to induce a significant conformational change which might prevent its association to DNA (or cause an existing DNA-protein complex to dissociate). In addition, as a consequence of the toxicity of free molecules of haem, we must assume that transcription factors acquire haem via ligand-substitution reactions from a chaperone; a protein that is suspected to moonlight as a haem chaperone is GAPDH. This project will investigate transient haem-protein interactions by utilizing structural biology to reveal the ligand-binding site, and different biophysical approaches to reveal the conformational dynamics of the transition between the apo and holo protein, along with mechanistic detail of haem-substitution reactions from an exemplar chaperone, GAPDH to an acceptor protein. 

Biomolecular assemblies in healthy development and cancer

Project leads: Yolanda Markaki, John Schwabe, James Hodgkinson and Cyril Dominguez

The nucleus is organized into membraneless, yet functionally distinct compartments. We now know that many nuclear compartments are organized by an array of non-coding RNAs implicated in diverse gene-regulatory processes including embryonic development, cell type-specific phenotypes and cancer. These RNAs acts as hubs/scaffolds for effector proteins forming complex biomolecular assemblies.

Intrinsically disordered regions (IDRs) have recently emerged as key players in the formation of biomolecular assemblies by driving weak, multivalent protein-protein interactions. We have previously identified that the IDRs of the transcriptional corepressor SPEN are essential for protein condensation within large ribonucleoprotein complexes. This supramolecular aggregation is essential for gene regulation. However, how IDR interactions form, their selectivity and contribution to multivalency or how interactions are perturbed in disease remains unclear.

This project will employ a multidisciplinary approach across scales to elucidate the function of these assemblies, their molecular organization, dynamic protein-protein and RNA-protein interactions. We will integrate state-of-the-art methods in stem cell biology and genome editing with super-resolution microscopy, biophysical and structural methods. We will use is silico structure predictions to determine the IDR-containing region(s) that are critical for self-interaction and condensation. We will express minimal RNA-protein assemblies and conduct structural studies by cryo-EM and NMR. We will next perturb these interactions, in vitro through peptide inhibitors which will guide in vivo genetic perturbations followed by downstream analyses within cells by super-resolution microscopy and quantitative image analyses. These pipelines will be significant towards the generation of imaging biomarkers with relevance in dysregulation of biomolecular condensates in cancer.

Defining how reactive metabolites regulate the protein cysteinome 

Project leads: Richard Hopkinson, Steve Bull and Chris Switzer

The biology of reactive metabolites (RMs) such as aldehydes and reactive oxygen and sulfur species is undetermined at the molecular level. This is largely because RMs are difficult to work with (reactive, small, unstable, volatile) and can exhibit different effects at different concentrations. To fully define the biology of RMs, a holistic multidisciplinary approach is required that combines chemical biology tools with cellular methods.

Cysteine is redox-sensitive and is the most nucleophilic amino acid under physiological conditions. It is therefore the most likely amino acid on proteins to undergo reactions with RMs. There are a growing number of reported RM-cysteine reactions on proteins, with many reported to induce functional changes. Many cysteine modifications are also reported to occur in disease and ageing. Understanding how RMs react with and affect the functions of cysteine-containing proteins is therefore of interest to basic science and biomedically focused research.

In this work, we will use bespoke RM-modulating chemical tools and imaging/detection methods to identify, characterise and phenotypically analyse RM reactions on cellular protein cysteines. Development of tool compounds will build on our previous expertise with aldehydes, reactive sulfur species and peroxynitrite, while the cellular work will use newly developed CRISPR methodology to screen for functionally relevant modifications. We will also monitor cysteine modifications (and selenocysteine modifications) in mouse models of ageing and oxidative stress. Ultimately the work will provide the first comprehensive overview of RM-mediated regulation of cysteines that should lead to new treatments against human disease.   

Structural investigation of the intrinsically disordered regions of the RNA binding protein Sam68: implication for RNA binding and phosphorylation

Project leads: Cyril Dominguez and Andrew Hudson

Intrinsically disordered regions (IDRs) or protein play crucial roles in almost all cellular functions. Still, the molecular mechanisms that govern their functions remains largely unknown. In recent years, classical structural and biophysical techniques (NMR, FRET, SAXS, ...) have been combined with molecular dynamics simulations to generate structural ensembles and derive the mechanisms of their functions.

Sam68 is a typical RNA binding protein that contains a classical folded RNA binding domain flanked by N-terminal and a C-terminal IDRs. While these IDRs have been shown to be crucial for the function of Sam68 and are targets of multiple post-translational modifications, the molecular mechanisms of their contribution remains unknown.

Our published (Malki et al, NAR, 2022) and preliminary data clearly show that the Nter and Cter IDRs of Sam68 have the ability to bind RNA specifically and that phosphorylation of a single threonine residue inhibits their RNA binding ability and consequently the cellular functions on the protein.

This raises three important questions:

1. How does an unstructured protein region bind specifically an unstructured RNA? What are the molecular basis for the specificity?
2. How does phosphorylation of a single-amino acid have such an impact on the RNA binding properties of the protein?
3. How does full-length Sam68 recognize specifically its RNA targets

We will answer these questions by combining the team expertise in structural and biophysical methods (NMR, FCS, FRET, SAXS) with molecular dynamics to decipher the structural properties of these regions free, in complex with RNA and following phosphorylation.

PhD opportunities

Funding

External funding for PhD positions is available through the schemes below. Students who are interested in doing doctoral research at the Institute are encouraged to apply to these and get in touch with Dr Tennie Videler (email hv33@le.ac.uk) beforehand. We can support you to put in the strongest possible application as these are very competitive.

BBSRC MIBTP

MIBTP is a BBSRC-funded Doctoral Training Partnership (DTP) between the University of Warwick, the University of Birmingham, the University of Leicester, Aston University and Harper Adams University with an emphasis on interdisciplinarity. The application window will open in December.

MRC Advanced Inter-disciplinary Models (AIM)

AIM is a Doctoral Training Programme funded by the MRC between the Universities of Birmingham, Nottingham, and Leicester. Doctoral students benefit from a diverse range of skills within the cohort, stimulating students to think ‘outside the box’ and perform innovative, world-leading research. The partner universities contribute project ideas, which prospective doctoral students choose from. The application window will open in December.

Doctoral Training Programme

To introduce PhD students to the full extent of technical capabilities and resources in the Institute of Structural and Chemical Biology, we have established a doctoral training programme for each new PhD cohort. By following this training element in the research degree, we hope for students to develop independence and a critical way of thinking, and become equipped with technical expertise beyond the specific tools and method used in their projects. The first year of the training programme is focussed on building skills across a broad range of techniques in structural and chemical biology. Subsequent years of the training programme are focussed on transferable skills, building independence and preparation for post-degree careers.

Job opportunities

We are always looking to explore options of gaining fantastic new colleagues. Please get in touch with Tennie at hv33@le.ac.uk or individual academics to discuss.

Why the Institute of Structural and Chemical Biology?

Profit from the informed teaching fuelled by the cutting-edge research at the Institute

• Access to the world class facilities at the Institute as well as the facilities at the University such as the award-winning David Wilson Library
• Members within the Institute will also benefit from the expertise and support from the Departments of Chemistry, Molecular and Cell  Biology and Respiratory Sciences.