Publications

Brian Ho’s group recently published a paper in PLOS Journal on 18th July 2024.

Interbacterial competition plays an important role in the dynamics of microbial communities, however the impact of such competition on host defenses is less clear. In this work, we use a zebrafish model to reductively investigate the host response to distinct forms of bacterial antagonism in well-defined bacterial communities. We looked at bacterial killing mediated by the type VI secretion system (T6SS) and observed that this form of bacterial antagonism resulted in prolonged inflammatory responses and an increase in host death, independent of any specific effector or bacterial species. By contrast, bacterial killing mediated by colicins, despite being significantly more efficient in eliminating sensitive bacteria, induced minimal host responses, resulting in a substantially better host outcome. Altogether, these results provide insight into the roles of different antibacterial systems that pathogens and commensals use inside their host.

Full paper can be accessed here.

Kristine Arnvig’s research group recently published a paper in the Nucleic Acids Journal. Full paper can be accessed here (doi.org/10.1093/nar/gkae338) .

Unexpected complexity of vitamin B12-sensing RNA elements in Mycobacterium tuberculosis.

The bacterium Mycobacterium tuberculosis (Mtb) lacks the ability to produce vitamin B12, yet this co-factor plays a significant role in Mtb’s metabolism and gene regulation. Research conducted by Tine Arnvig’s team reveals an intriguing additional layer of control exerted by vitamin B12-sensing RNA elements, known as riboswitches, over metabolic and virulence genes in this pathogen. Beyond uncovering the B12-dependent inhibition of translation initiation, the team also uncovered two novel translated uORFs, which influence riboswitch regulation. In one instance, they identified a crucial translational link between the uORF and its downstream gene, facilitating translation re-initiation independently of Shine-Dalgarno sequences, alongside stop codon suppression, resulting in the synthesis of a frameshifted fusion protein. Essentially, Mtb demonstrates the capacity to generate similar proteins with differing N-termini, akin to eukaryotic alternative splicing. Lead author Dr. Terry Kipkorir remarks, “[This] represents yet another example of how Mtb breaks the mould in our understanding of gene expression control.’

The prevalent state of DNA in all cells is chromatin that is made of protein-DNA complexes which are dynamic, complex and heterogenous. The exact composition of the chromatin determines its properties, how it regulates transcription and genome architecture. A breakthrough article by the RNAP laboratory at UCL published today in the journal Nature Communications describes how two chromatin proteins, Cbp1 and Cren7, collaborate to modulate gene regulation in opposing ways. While this type of specialised chromatin stimulates the expression of long crRNA arrays that facilitate adaptive immunity in archaea (‘CRISPR’), it cryptic promoters that frequently reside in the memory of the ‘immunity’ system, in the ‘CRISPR spacers’. This transcription interference by cryptic promoters limits how much spacer information can be stored in CRISPR arrays, or worse lead the malfunction of the system. Dr. Fabian Blombach from the ISMB RNAP laboratory, the lead author of the study, says ‘There is a lot of attention in the field to histones and their role in gene regulation, but we can learn so much from archaeal and bacterial chromatin proteins, including some of the ground rules that shape the interaction between chromatin proteins and transcription in all cellular life.’

Sulfolobus Cbp1 and Cren7 form chimeric chromatin structures on large archaeal CRISPR arrays. Cbp1 confers sequence-specificity and interacts via its HTH3 domain interactions with Cren7. Together, they enhance leader promoters but repress CRISPR spacer-encoded cryptic promoters¹. Archaea research in the RNAP lab is funded by the Wellcome Trust Investigator in Science Award (WT207446/Z/17/Z).

References

1. Blombach, F., Sykora, M., Case, J., Feng, X., Baquero, D.P., Fouqueau, T., Phung, D.K., Barker, D., Krupovic, M., She, Q., and Werner, F. (2024). Cbp1 and Cren7 form chromatin-like structures that ensure efficient transcription of long CRISPR arrays. Nat Commun 15, 1620. 10.1038/s41467-024-45728-8.

Full paper can be read here.

Together with the Topf lab at the Centre for Structural Systems Biology (Hamburg), Kish Adoni from the Thalassinos lab has developed a novel pipeline that incorporates crosslinking-mass spectrometry data into AlphaFold2 for improved accuracy of protein structure determination. They found this workflow to be of particular relevance to proteins that occupy multiple conformations. The function of a protein is determined by its structure, via the structure-function relationship, and thousands of proteins modify their shape upon external cues such as molecular or protein interactions. As such, probing these conformational modifications is pivotal to characterising the protein’s behaviour, for example in the context of drug design when developing pharmaceuticals for drug-protein interactions.

Full paper can be read here.

Professor Helen Saibil’s research group published a paper titled ‘Structural basis of substrate progression through the bacterialchaperonin cycle’ in the PNAS Journal on 23 October 2023.
The full paper is available here.

Dr Joseph Ng and Prof. Franca Fraternali have published the novel method sciCSR to analyse CSR (class-switch recombination) and the antibody response by using molecular data from single B-cells (Nature Methods). 

Flemming Hansen’s research group published a paper titled ‘Intrinsic structural dynamics dictate enzymatic activity and inhibition’ in the Proceedings of the National Academy of Sciences (PNAS) Journal on 2 October 2023.
The full paper is available here.

Professor Kostas Thalassinos’ research group published a paper titled ‘Genomic investigations of unexplained acute hepatitis in children’ in the Nature Journal on 30 March 2023.
The full paper is available here.

Professor Helen Saibil’s research group published a paper titled ‘Structural journey of an insecticidal protein against western corn rootworm’ in Nature Communications on 13 July 2023. The full paper is available here.

Her group published two other papers recently, the paper titled ‘Structural basis of ubiquitin-independent PP1 complex disassembly by p97’ was published in The EMBO Journal on 2 June 2023. The full paper is available here.

Finally, a paper on ‘A structural basis for prion strain diversity’ was published in the Nature Chemical Biology on 16 January 2023. The full paper is available here.