Completed Cells, Biochemistry & Physiology Genetics & Molecular Biology

Functional organization, regulation and cellular roles of elongation factor (eEF) 2 kinase.

Funder Wellcome Charity-funded
Associated organisations Misc Australia · University of Southampton Europe PMC affiliations are not treated as award recipients or mapped locations.
Funding £1.3M
Period Apr 2009 — Oct 2016

In plain English

AI plain-English summary

Every cell in the human body must build proteins on demand, and a single enzyme called eEF2 kinase acts as a master brake on that process. This project aims to map exactly how that brake is applied and released. The problem is that while scientists know eEF2 kinase stops protein production when cells are stressed, low on energy, or responding to hormones, the molecular switches that control the kinase itself remain poorly understood. Without that knowledge, researchers cannot predict—let alone manipulate—how cells adjust their protein output in disease. This is fundamental science. The researchers will identify the specific chemical modifications that turn eEF2 kinase on and off, determine how changes in acidity affect it, and search for other proteins it might control. They will use cells and animals genetically engineered to lack the kinase to see what goes wrong. If successful, this work will provide a wiring diagram for a central regulator of protein synthesis. That could eventually inform drug design for conditions where protein production goes awry—cancer, neurodegeneration, or metabolic disorders—but the immediate payoff is a deeper understanding of a core cellular machine.

View original technical description
This proposal concerns the unusual protein kinase that regulates the activity of elongation factor eEF2, i.e., eEF2 kinase (eEF2K). It builds upon recent advances in this area in the applicants laboratories. The main goals of this Programme are: 1. to establish how signalling through mTOR complex 1 (mTORC1) regulates the activity of eEF2K; in particular to identify the kinase that acts at Ser78 in eEF2K; 2. to determine how (auto)phosphorylation controls eEF2K activity and to identify add itional regulatory phosphorylation sites within eEF2K; 3. to elucidate how other regulatory inputs, such as pH, control eEF2K and their importance for the control of eEF2 and protein synthesis; 4. (i) to study the structures and functions of different domains within eEF2K and (ii) to investigate the interactions and interplay between them in the function of eEF2K and its control; 5. to explore the roles of eEF2K and the phosphorylation of eEF2 in regulating protein synthesis in response to hormones and growth factors or under conditions of cellular stress such as ATP depletion. This exploits the availability of cells, tissues and animals that lack eEF2K activity; 6. to determine whether eEF2K plays additional physiological roles and identify new substrates for this kinase.

View the original record at the funder ↗

Researchers

Christopher Proud (EPMC Awardee)Joern Werner (EPMC Awardee)

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Original classification

Programme Grant

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