MRC National Institute for Medical Research, London
Science for Health
Integrating signalling and mRNA metabolism
13 February 2009
Messenger RNA (mRNA) metabolism is regulated in response to a signal to allow a fast and localised tuning of protein synthesis. Phosphorylation plays a major role in integrating signalling pathways and mRNA metabolism, but the molecular features of this integration are unclear. In some cases phosphorylation has been associated with changes in the mRNA binding capability of the protein, in others with a variation of its protein partners.
KH-type splicing regulatory protein (KSRP) is a multifunctional RNA binding protein that recruits the cytoplasmic exosome degradation machinery to a subset of target mRNAs. This leads to mRNA degradation and downregulation of genes that control inflammation and cellular proliferation. The KSRP-dependent decay mechanism is inhibited by AKT phosphorylation, an effect mediated by KSRP binding to a small acidic protein called 14-3-3ζ that recognises phosphoserine/phosphothreonine within a short and unfolded peptide sequence.
Andres Ramos (pictured) and members of his laboratory along with colleagues from the MRC Biomedical NMR Centre and the Division of Physical Biochemistry, have shown that the action of the kinase AKT is mediated by the unfolding of the first KH domain of KSRP. This domain contains the kinase target site and has an intrinsically low stability. Phosphorylation by AKT traps it in an unfolded conformation, creating a site for 14-3-3ζ binding. Binding leads to nuclear localisation of KSRP and impairs mRNA decay.
Dr Ramos said:
mRNA decay and translational repression are regulated in a coordinated way, with functionally related mRNAs grouped in RNA-protein particles by regulatory proteins. By targeting these regulatory proteins it may be possible to control the expression of genes involved in cellular proliferation. Using existing signal transduction mechanisms would facilitate this task. The - so far - sparse data on post-translational regulation of mRNA metabolism indicate that large conformational changes and changes in inter-domain interactions may play a major role in signal transduction. Our work reveals a new mechanism of regulation, where phosphorylation-driven domain unfolding creates a site for the binding of an adaptor protein. This observation highlights the functional flexibility of RNA binding domains and suggests that plasticity of structure and interaction network could provide us with very specific tools to control mRNA metabolism and therefore the synthesis of proteins involved in cell proliferation and inflammation.
Original article
The research findings are published in full in:
Irene Díaz-Moreno, David Hollingworth, Thomas A Frenkiel, Geoff Kelly, Stephen Martin, Steven Howell, MaríaFlor Garcia-Mayoral, Roberto Gherzi, Paola Briata and Andres Ramos (2009)
Phosphorylation-mediated unfolding of a KH domain regulates KSRP localization via 14-3-3 binding
Nature Structural and Molecular Biology Epub ahead of print. Publisher abstract
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