Molecules and their markers

Understanding evolution using molecules and their markers

Robert Gilbert with Xiulian Yu, Milda Zilnyte and Gangshun Yi

Our project is asking how studies of atomic structures and macromolecular assemblies can help us understand evolution in deep time, and how lifetime experience imprints itself on cell biology through epigenetic changes and protein modification in cells.

To do this we study and interpret the atomic structures of proteins and their complexes important in infection and immunity and in the control of cell fate. Our principal methods include X-ray crystallography and cryo-electron microscopy, with associated computational analyses of data and structural models.

One set of molecules we study is a family of pore-forming proteins which have evolved to attack cell membranes and cause the death of target cells. Bacterial pathogens such as the pneumococcus make members of this family of pore-forming proteins and so do parasites causing disease in humans such as toxoplasma and the malarial parasite plasmodium. But at the same time humans and all animals make evolutionarily-related proteins which provide mechanisms of innate and adaptive immunity. A further sub-set of this family of proteins – specific to vertebrates – are not thought to form pores at all but are involved in neurodevelopmental process, especially in the brain. We are studying members of the pathogenic, immunity and developmental sub-groups of these perforin and perforin-like proteins.

Another process we study is the control of gene expression through epigenetic and genetic switches. A particular focus here is a set of enzymes which target small RNA signalling molecules controlling cell fate. Suppression of these microRNA signals leads, in some well-defined cases, to cancers affecting a variety of organs.

Publications to date:

“Cryo-EM structures of perforin-2 in isolation and assembled on a membrane suggest a mechanism for pore formation.” Yu X., Ni T., Munson G., Zhang P., Gilbert R.J.C. The EMBO Journal (2022) 17:e111857. LINK

“Structural, Functional and Computational Studies of Membrane Recognition by Plasmodium Perforin-Like Proteins 1 and 2.” Williams S.I., Yu X., Ni T., Gilbert R.J.C., Stansfeld P.J. Journal of Molecular Biology (2022) 434:167642. LINK

“Structure and mechanism of bactericidal mammalian perforin-2, an ancient agent of innate immunity.”.Ni T., Jiao F., Yu X., Aden S., Ginger L., Williams S.I., Bai F., Pražák V., Karia D., Stansfeld P.J., Zhang P., Munson G., Anderluh G., Scheuring S., Gilbert R.J.C. (2020) Science Advances 6:eaax8286. LINK

“Structures of monomeric and oligomeric forms of the Toxoplasma gondii perforin-like protein 1.” Ni T., Williams S.I., Rezelj S., Anderluh G., Harlos K., Stansfeld P.J., Gilbert R.J.C. Science Advances (2018) 4:eaaq0762. LINK