MRC National Institute for Medical Research, London

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Migrating neurons in the cerebral cortex

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Genetics and Development

Infections and Immunity

Neurosciences

Structural Biology

Andres Ramos group

Molecular recognition in post-transcriptional regulation

Post-transcriptional regulation allows fine tuning of gene expression in complex organisms. Impaired regulatory mechanisms have been linked to cancer, autoimmune and neurodegenerative diseases and viral infection. A molecular understanding of these regulatory mechanisms and of the connection with transcriptional and post-translational regulatory networks is the first step to exploit the potential of protein-RNA regulatory systems in the development of anti-viral and anti-cancer drugs.

Multi-component protein-RNA particles (RNPs) provide a functional connection between the different steps of mRNA metabolism and coordinate post-transcriptional regulation. The assembly of these particles relies on specific protein-protein and protein-RNA recognition events and is regulated both by the action of non-coding RNAs (e.g. miRNAs) and by post-translational modifications (e.g. phosphorylation and methylation) of the proteins involved. Further, recent studies have shown that the protein involved play often a role in itranscriptional regulation, establishing a connection between different steps of gene regulation.

We provide a molecular rationale for protein-protein and protein-RNA recognition within RNPs using a multi-disciplinary approach, applying NMR and other of structural and biophysical techniques (x-ray crystallography, analytical ultracentrifugation, mass spectrometry, circular dichroism, cryoEM etc.) to study these interactions and coordinating our work with in cell/in vivo assays. We are also exploring the the protein-protein and protein-DNA interactions mediated by the same proteins during transcriptional regulation.

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¹⁵N-¹H correlation NMR spectra of KSRP KH3, KH23 and KH34 when bound to Let-7a miRNA TL.

Research projects

Selected publications

Cukier, CD; Hollingworth, D; Martin, SR; Kelly, G; Díaz-Moreno, I and Ramos, A (2010)
Molecular basis of FIR-mediated c-myc transcriptional control.
Nature Structural & Molecular Biology Epub ahead of print, PubMed abstract
Trabucchi, M; Briata, P; Garcia-Mayoral, M; Haase, AD; Filipowicz, W; Ramos, A; Gherzi, R and Rosenfeld, MG (2009)
The RNA-binding protein KSRP promotes the biogenesis of a subset of microRNAs.
Nature 459, 1010-1014 PubMed abstract
Díaz-Moreno, I; Hollingworth, D; Frenkiel, TA; Kelly, G; Martin, S; Howell, S; García-Mayoral, M; Gherzi, R; Briata, P and Ramos, A (2009)
Phosphorylation-mediated unfolding of a KH domain regulates KSRP localization via 14-3-3 binding.
Nature Structural & Molecular Biology 16, 238-246 PubMed abstract
García-Mayoral, MF; Díaz-Moreno, I; Hollingworth, D and Ramos, A (2008)
The sequence selectivity of KSRP explains its flexibility in the recognition of the RNA targets.
Nucleic Acids Research 36, 5290-5296 PubMed abstract
Beuth, B; García-Mayoral, MF; Taylor, IA and Ramos, A (2007)
Scaffold-independent analysis of RNA-protein interactions: The Nova-1 KH3-RNA complex.
Journal of the American Chemical Society 129, 10205-10 PubMed abstract
Noble, CG; Hollingworth, D; Martin, SR; Ennis-Adeniran, V; Smerdon, SJ; Kelly, G; Taylor, IA and Ramos, A (2005)
Key features of the interaction between Pcf11 CID and RNA polymerase II CTD.
Nature Structural & Molecular Biology 12, 144-151 PubMed abstract