Wellcome Senior Research Fellow
Atlanta Cook is a Senior Research Fellow funded by the Wellcome Trust. Her group studies the mechanistic basis of post-transcriptional control of gene expression using biochemical and structural approaches. She did her PhD on mechanistic studies of protein kinases with Dame Prof. Louise Johnson in Oxford. She joined the laboratory of Elena Conti in 2004 to work on the structural basis of tRNA export at the EMBL in Heidelberg. She completed this work after moving with the Conti laboratory to the MPI for Biochemistry in Martinsried near Munich. She started her group in Edinburgh in 2011, funded by an MRC Career Development Award. In 2017 she was awarded an Early Career Researcher prize from the British Crystallographic Association.
Structural biology of macromolecular complexes involved in RNA metabolism and transcriptional silencing
The expression of individual genes is controlled at the levels of mRNA transcription and also post-transcriptionally, by processes such as splicing, localization, modification or editing, and degradation. To gain a mechanistic understanding of these processes it is important to understand the interactions between the individual players, including both protein and nucleic acid components, at the molecular level. We have used structural approaches to tackle mechanistic questions about how protein-RNA interactions can control RNA maturation and RNA editing and how transcriptional repressors are recruited to methylated DNA. By combining structural studies with biochemical, biophysical and cell-based functional assays we can gain powerful insights into these molecular processes.
We have contributed to the understanding of the molecular basis for the neurological disease known as Rett syndrome, which is caused by mutations in the DNA binding protein MeCP2. In collaboration with Adrian Bird’s lab, we showed that a cluster of Rett syndrome associated missense mutations on MeCP2 are part of a motif that binds to a component of a nuclear co-repressor complex. This interaction supports a model where MeCP2 acts a bridge between methylated DNA and complexes that drive gene repression.
Recently, we solved a crystal structure of a yeast RNA binding protein, Ssd1, that is important in cell wall biogenesis. It is thought that Ssd1 functions by repressing translation of cognate transcripts. Using CRAC, we found that Ssd1 binds to specific sequences in the 5’UTRs of a small set of transcripts, several of which encode proteins required for cell wall biogenesis. The structure of Ssd1 shows that it has a classical fold of an RNase II family nuclease. However, RNA degradation activity has been lost by two mechanisms. First, the catalytic residues have been altered during evolution. Second, a channel that, in active enzymes, allows RNA substrates to funnel into the active site has been blocked. We propose that Ssd1 has evolved a new RNA interacting surface.
Pantier R., Chhatbar K., Quante T., Skourti-Stathaki K., Cholewa-Waclaw J., Alston G., Alexander-Howden B., Lee H.Y., Cook A.G., C Spruijt C.G., Vermeulen M., Selfridge J., and Bird A. (2021) SALL4 controls cell fate in response to DNA base composition. Mol Cell
Ballou E.R., Cook A.G. and Wallace E.W.J. (2020) Repeated evolution of inactive pseudonucleases in a fungal branch of the Dis3/RNase II family of nucleases. Mol. Biol. Evol. doi:10.1093/molbev/msaa324
Zoch, A., Auchynnikava T., Berrens R.V., Kabayama Y., Schöpp T., Heep M., Vasiliauskaite L., Pérez-Rico Y.A., Cook A.G., Shkumatava A., Rappsilber J., Allshire R.C. and O'Carroll D. (2020) SPOCD1 is an essential executor of piRNA-directed de novo DNA methylation Nature 584:635-639.
A domain overview of Ssd1 is shown along with the crystal structure with domains marked in blue, cyan, green and pink. The Ssd1-specific insert is shown in the domain overview and structure in orange. The yellow lollipops are phosphorylation sites. Two segments of the Ssd1 structure are shown in black – these block the active site funnel, as can be seen by comparison with the structure of DIS3L2 (left), where RNA is bound.