| Structural highlights
Function
EF2K_HUMAN Threonine kinase that regulates protein synthesis by controlling the rate of peptide chain elongation. Upon activation by a variety of upstream kinases including AMPK or TRPM7, phosphorylates the elongation factor EEF2 at a single site, renders it unable to bind ribosomes and thus inactive. In turn, the rate of protein synthesis is reduced.[1] [2]
Publication Abstract from PubMed
Eukaryotic elongation factor 2 kinase (eEF-2K) phosphorylates its only known physiological substrate, elongation factor 2 (eEF-2), which reduces the affinity of eEF-2 for the ribosome and results in an overall reduction in protein translation rates. The C-terminal region of eEF-2K, that is predicted to contain several SEL-1 like helical repeats (SLRs), is required for the phosphorylation of eEF-2. Using solution NMR methodology, we have determined the structure of a 99-residue fragment from the extreme C-terminus of eEF-2K (eEF-2K627-725) that encompasses a region previously suggested to be essential for eEF-2 phosphorylation. eEF-2K627-725 contains four helices, of which the first (I) is flexible, and does not pack stably against the ordered helical core formed by the last three helices (II-IV). The helical core shows significant structural similarity with members of the tetratricopeptide repeat (TPR) family that includes SLRs. The two penultimate helices, II and III, comprise the TPR, and the final helix, IV, appears to have a capping function. The eEF-2K627-725 structure illustrates that the C-terminal deletion that was shown to abolish eEF-2 phosphorylation does so by destabilizing IV and therefore, the helical core. Indeed, mutation of two conserved C-terminal tyrosines (Y712A/Y713A) in eEF-2K previously shown to abolish eEF-2 phosphorylation, leads to the unfolding of eEF-2K627-725. Preliminary functional analyses indicate that neither a peptide encoding a region deemed crucial for eEF-2 binding, nor isolated eEF-2K627-725 inhibit eEF-2 phosphorylation by full-length eEF-2K. Taken together, our data suggest that the extreme C-terminal region of eEF-2K, in isolation, does not provide a primary docking site for eEF-2.
Structure of the C-terminal Helical Repeat Domain of Eukaryotic Elongation Factor 2 Kinase.,Will N, Piserchio A, Snyder I, Ferguson SB, Giles DH, Dalby KN, Ghose R Biochemistry. 2016 Aug 29. PMID:27571275[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Browne GJ, Finn SG, Proud CG. Stimulation of the AMP-activated protein kinase leads to activation of eukaryotic elongation factor 2 kinase and to its phosphorylation at a novel site, serine 398. J Biol Chem. 2004 Mar 26;279(13):12220-31. Epub 2004 Jan 5. PMID:14709557 doi:10.1074/jbc.M309773200
- ↑ Ryazanov AG, Ward MD, Mendola CE, Pavur KS, Dorovkov MV, Wiedmann M, Erdjument-Bromage H, Tempst P, Parmer TG, Prostko CR, Germino FJ, Hait WN. Identification of a new class of protein kinases represented by eukaryotic elongation factor-2 kinase. Proc Natl Acad Sci U S A. 1997 May 13;94(10):4884-9. PMID:9144159
- ↑ Will N, Piserchio A, Snyder I, Ferguson SB, Giles DH, Dalby KN, Ghose R. Structure of the C-terminal Helical Repeat Domain of Eukaryotic Elongation Factor 2 Kinase. Biochemistry. 2016 Aug 29. PMID:27571275 doi:http://dx.doi.org/10.1021/acs.biochem.6b00711
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