The Molecular Mechanism of Eukaryotic Elongation Factor 2 Kinase Activation
Calmodulin (CaM)-dependent eukaryotic elongation factor 2 kinase (eEF-2K) impedes protein synthesis through phosphorylation of eukaryotic elongation factor 2 (eEF-2). It is subject to complex regulation by multiple upstream signaling pathways, through poorly described mechanisms. Precise integration...
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| Published in | The Journal of biological chemistry Vol. 289; no. 34; pp. 23901 - 23916 |
|---|---|
| Main Authors | , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Elsevier Inc
22.08.2014
American Society for Biochemistry and Molecular Biology |
| Subjects | |
| Online Access | Get full text |
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| Abstract | Calmodulin (CaM)-dependent eukaryotic elongation factor 2 kinase (eEF-2K) impedes protein synthesis through phosphorylation of eukaryotic elongation factor 2 (eEF-2). It is subject to complex regulation by multiple upstream signaling pathways, through poorly described mechanisms. Precise integration of these signals is critical for eEF-2K to appropriately regulate protein translation rates. Here, an allosteric mechanism comprising two sequential conformations is described for eEF-2K activation. First, Ca2+/CaM binds eEF-2K with high affinity (Kd(CaM)app = 24 ± 5 nm) to enhance its ability to autophosphorylate Thr-348 in the regulatory loop (R-loop) by > 104-fold (kauto = 2.6 ± 0.3 s−1). Subsequent binding of phospho-Thr-348 to a conserved basic pocket in the kinase domain potentially drives a conformational transition of the R-loop, which is essential for efficient substrate phosphorylation. Ca2+/CaM binding activates autophosphorylated eEF-2K by allosterically enhancing kcatapp for peptide substrate phosphorylation by 103-fold. Thr-348 autophosphorylation results in a 25-fold increase in the specificity constant (kcatapp/Km(Pep-S)app), with equal contributions from kcatapp and Km(Pep-S)app, suggesting that peptide substrate binding is partly impeded in the unphosphorylated enzyme. In cells, Thr-348 autophosphorylation appears to control the catalytic output of active eEF-2K, contributing more than 5-fold to its ability to promote eEF-2 phosphorylation. Fundamentally, eEF-2K activation appears to be analogous to an amplifier, where output volume may be controlled by either toggling the power switch (switching on the kinase) or altering the volume control (modulating stability of the active R-loop conformation). Because upstream signaling events have the potential to modulate either allosteric step, this mechanism allows for exquisite control of eEF-2K output. |
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| AbstractList | Calmodulin (CaM)-dependent eukaryotic elongation factor 2 kinase (eEF-2K) impedes protein synthesis through phosphorylation of eukaryotic elongation factor 2 (eEF-2). It is subject to complex regulation by multiple upstream signaling pathways, through poorly described mechanisms. Precise integration of these signals is critical for eEF-2K to appropriately regulate protein translation rates. Here, an allosteric mechanism comprising two sequential conformations is described for eEF-2K activation. First, Ca2+/CaM binds eEF-2K with high affinity (Kd(CaM)app = 24 ± 5 nm) to enhance its ability to autophosphorylate Thr-348 in the regulatory loop (R-loop) by > 104-fold (kauto = 2.6 ± 0.3 s−1). Subsequent binding of phospho-Thr-348 to a conserved basic pocket in the kinase domain potentially drives a conformational transition of the R-loop, which is essential for efficient substrate phosphorylation. Ca2+/CaM binding activates autophosphorylated eEF-2K by allosterically enhancing kcatapp for peptide substrate phosphorylation by 103-fold. Thr-348 autophosphorylation results in a 25-fold increase in the specificity constant (kcatapp/Km(Pep-S)app), with equal contributions from kcatapp and Km(Pep-S)app, suggesting that peptide substrate binding is partly impeded in the unphosphorylated enzyme. In cells, Thr-348 autophosphorylation appears to control the catalytic output of active eEF-2K, contributing more than 5-fold to its ability to promote eEF-2 phosphorylation. Fundamentally, eEF-2K activation appears to be analogous to an amplifier, where output volume may be controlled by either toggling the power switch (switching on the kinase) or altering the volume control (modulating stability of the active R-loop conformation). Because upstream signaling events have the potential to modulate either allosteric step, this mechanism allows for exquisite control of eEF-2K output. Calmodulin (CaM)-dependent eukaryotic elongation factor 2 kinase (eEF-2K) impedes protein synthesis through phosphorylation of eukaryotic elongation factor 2 (eEF-2). It is subject to complex regulation by multiple upstream signaling pathways, through poorly described mechanisms. Precise integration of these signals is critical for eEF-2K to appropriately regulate protein translation rates. Here, an allosteric mechanism comprising two sequential conformations is described for eEF-2K activation. First, Ca(2+)/CaM binds eEF-2K with high affinity (Kd(CaM)(app) = 24 ± 5 nm) to enhance its ability to autophosphorylate Thr-348 in the regulatory loop (R-loop) by > 10(4)-fold (k(auto) = 2.6 ± 0.3 s(-1)). Subsequent binding of phospho-Thr-348 to a conserved basic pocket in the kinase domain potentially drives a conformational transition of the R-loop, which is essential for efficient substrate phosphorylation. Ca(2+)/CaM binding activates autophosphorylated eEF-2K by allosterically enhancing k(cat)(app) for peptide substrate phosphorylation by 10(3)-fold. Thr-348 autophosphorylation results in a 25-fold increase in the specificity constant (k(cat)(app)/K(m)(Pep-S) (app)), with equal contributions from k(cat)(app) and K(m)(Pep-S)(app), suggesting that peptide substrate binding is partly impeded in the unphosphorylated enzyme. In cells, Thr-348 autophosphorylation appears to control the catalytic output of active eEF-2K, contributing more than 5-fold to its ability to promote eEF-2 phosphorylation. Fundamentally, eEF-2K activation appears to be analogous to an amplifier, where output volume may be controlled by either toggling the power switch (switching on the kinase) or altering the volume control (modulating stability of the active R-loop conformation). Because upstream signaling events have the potential to modulate either allosteric step, this mechanism allows for exquisite control of eEF-2K output.Calmodulin (CaM)-dependent eukaryotic elongation factor 2 kinase (eEF-2K) impedes protein synthesis through phosphorylation of eukaryotic elongation factor 2 (eEF-2). It is subject to complex regulation by multiple upstream signaling pathways, through poorly described mechanisms. Precise integration of these signals is critical for eEF-2K to appropriately regulate protein translation rates. Here, an allosteric mechanism comprising two sequential conformations is described for eEF-2K activation. First, Ca(2+)/CaM binds eEF-2K with high affinity (Kd(CaM)(app) = 24 ± 5 nm) to enhance its ability to autophosphorylate Thr-348 in the regulatory loop (R-loop) by > 10(4)-fold (k(auto) = 2.6 ± 0.3 s(-1)). Subsequent binding of phospho-Thr-348 to a conserved basic pocket in the kinase domain potentially drives a conformational transition of the R-loop, which is essential for efficient substrate phosphorylation. Ca(2+)/CaM binding activates autophosphorylated eEF-2K by allosterically enhancing k(cat)(app) for peptide substrate phosphorylation by 10(3)-fold. Thr-348 autophosphorylation results in a 25-fold increase in the specificity constant (k(cat)(app)/K(m)(Pep-S) (app)), with equal contributions from k(cat)(app) and K(m)(Pep-S)(app), suggesting that peptide substrate binding is partly impeded in the unphosphorylated enzyme. In cells, Thr-348 autophosphorylation appears to control the catalytic output of active eEF-2K, contributing more than 5-fold to its ability to promote eEF-2 phosphorylation. Fundamentally, eEF-2K activation appears to be analogous to an amplifier, where output volume may be controlled by either toggling the power switch (switching on the kinase) or altering the volume control (modulating stability of the active R-loop conformation). Because upstream signaling events have the potential to modulate either allosteric step, this mechanism allows for exquisite control of eEF-2K output. Calmodulin (CaM)-dependent eukaryotic elongation factor 2 kinase (eEF-2K) impedes protein synthesis through phosphorylation of eukaryotic elongation factor 2 (eEF-2). It is subject to complex regulation by multiple upstream signaling pathways, through poorly described mechanisms. Precise integration of these signals is critical for eEF-2K to appropriately regulate protein translation rates. Here, an allosteric mechanism comprising two sequential conformations is described for eEF-2K activation. First, Ca(2+)/CaM binds eEF-2K with high affinity (Kd(CaM)(app) = 24 ± 5 nm) to enhance its ability to autophosphorylate Thr-348 in the regulatory loop (R-loop) by > 10(4)-fold (k(auto) = 2.6 ± 0.3 s(-1)). Subsequent binding of phospho-Thr-348 to a conserved basic pocket in the kinase domain potentially drives a conformational transition of the R-loop, which is essential for efficient substrate phosphorylation. Ca(2+)/CaM binding activates autophosphorylated eEF-2K by allosterically enhancing k(cat)(app) for peptide substrate phosphorylation by 10(3)-fold. Thr-348 autophosphorylation results in a 25-fold increase in the specificity constant (k(cat)(app)/K(m)(Pep-S) (app)), with equal contributions from k(cat)(app) and K(m)(Pep-S)(app), suggesting that peptide substrate binding is partly impeded in the unphosphorylated enzyme. In cells, Thr-348 autophosphorylation appears to control the catalytic output of active eEF-2K, contributing more than 5-fold to its ability to promote eEF-2 phosphorylation. Fundamentally, eEF-2K activation appears to be analogous to an amplifier, where output volume may be controlled by either toggling the power switch (switching on the kinase) or altering the volume control (modulating stability of the active R-loop conformation). Because upstream signaling events have the potential to modulate either allosteric step, this mechanism allows for exquisite control of eEF-2K output. Background: Eukaryotic elongation factor 2 kinase (eEF-2K) regulates protein translation elongation rates. Results: eEF-2K activation involves a two-step process of calmodulin binding and rapid Thr-348 autophosphorylation. Conclusion: Activation of eEF-2K involves two distinct allosteric steps, both of which potentially induce a conformational change. Significance: This mechanism provides a framework for understanding how eEF-2K integrates inputs from multiple upstream signaling pathways. Calmodulin (CaM)-dependent eukaryotic elongation factor 2 kinase (eEF-2K) impedes protein synthesis through phosphorylation of eukaryotic elongation factor 2 (eEF-2). It is subject to complex regulation by multiple upstream signaling pathways, through poorly described mechanisms. Precise integration of these signals is critical for eEF-2K to appropriately regulate protein translation rates. Here, an allosteric mechanism comprising two sequential conformations is described for eEF-2K activation. First, Ca 2+ /CaM binds eEF-2K with high affinity ( K d (CaM) app = 24 ± 5 n m ) to enhance its ability to autophosphorylate Thr-348 in the regulatory loop (R-loop) by > 10 4 -fold ( k auto = 2.6 ± 0.3 s −1 ). Subsequent binding of phospho-Thr-348 to a conserved basic pocket in the kinase domain potentially drives a conformational transition of the R-loop, which is essential for efficient substrate phosphorylation. Ca 2+ /CaM binding activates autophosphorylated eEF-2K by allosterically enhancing k cat app for peptide substrate phosphorylation by 10 3 -fold. Thr-348 autophosphorylation results in a 25-fold increase in the specificity constant ( k cat app / K m (Pep-S) app ), with equal contributions from k cat app and K m (Pep-S) app , suggesting that peptide substrate binding is partly impeded in the unphosphorylated enzyme. In cells, Thr-348 autophosphorylation appears to control the catalytic output of active eEF-2K, contributing more than 5-fold to its ability to promote eEF-2 phosphorylation. Fundamentally, eEF-2K activation appears to be analogous to an amplifier, where output volume may be controlled by either toggling the power switch (switching on the kinase) or altering the volume control (modulating stability of the active R-loop conformation). Because upstream signaling events have the potential to modulate either allosteric step, this mechanism allows for exquisite control of eEF-2K output. |
| Author | Tavares, Clint D.J. Warthaka, Mangalika Wang, Qiantao Giles, David H. Brodbelt, Jennifer S. Dalby, Kevin N. O'Brien, John P. Ren, Pengyu Ferguson, Scarlett B. Wellmann, Rebecca M. |
| Author_xml | – sequence: 1 givenname: Clint D.J. surname: Tavares fullname: Tavares, Clint D.J. email: clinttavares@utexas.edu organization: Graduate Program in Cell and Molecular Biology, University of Texas, Austin, Texas 78712 – sequence: 2 givenname: Scarlett B. surname: Ferguson fullname: Ferguson, Scarlett B. organization: Division of Medicinal Chemistry, College of Pharmacy, University of Texas, Austin, Texas 78712 – sequence: 3 givenname: David H. surname: Giles fullname: Giles, David H. organization: Division of Medicinal Chemistry, College of Pharmacy, University of Texas, Austin, Texas 78712 – sequence: 4 givenname: Qiantao surname: Wang fullname: Wang, Qiantao organization: Division of Medicinal Chemistry, College of Pharmacy, University of Texas, Austin, Texas 78712 – sequence: 5 givenname: Rebecca M. surname: Wellmann fullname: Wellmann, Rebecca M. organization: Division of Medicinal Chemistry, College of Pharmacy, University of Texas, Austin, Texas 78712 – sequence: 6 givenname: John P. surname: O'Brien fullname: O'Brien, John P. organization: Department of Chemistry and Biochemistry, College of Natural Sciences, University of Texas, Austin, Texas 78712 – sequence: 7 givenname: Mangalika surname: Warthaka fullname: Warthaka, Mangalika organization: Division of Medicinal Chemistry, College of Pharmacy, University of Texas, Austin, Texas 78712 – sequence: 8 givenname: Jennifer S. surname: Brodbelt fullname: Brodbelt, Jennifer S. organization: Department of Chemistry and Biochemistry, College of Natural Sciences, University of Texas, Austin, Texas 78712 – sequence: 9 givenname: Pengyu surname: Ren fullname: Ren, Pengyu organization: Department of Biomedical Engineering, Cockrell School of Engineering, and University of Texas, Austin, Texas 7871 – sequence: 10 givenname: Kevin N. surname: Dalby fullname: Dalby, Kevin N. email: dalby@austin.utexas.edu organization: Graduate Program in Cell and Molecular Biology, University of Texas, Austin, Texas 78712 |
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| Issue | 34 |
| Keywords | Phosphorylation Translation Calcium eEF-2 Allosteric Regulation eEF-2K Thr-348 Calmodulin (CaM) Phosphate-binding Pocket CaMK-III |
| Language | English |
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| Snippet | Calmodulin (CaM)-dependent eukaryotic elongation factor 2 kinase (eEF-2K) impedes protein synthesis through phosphorylation of eukaryotic elongation factor 2... Background: Eukaryotic elongation factor 2 kinase (eEF-2K) regulates protein translation elongation rates. Results: eEF-2K activation involves a two-step... |
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| SubjectTerms | Amino Acid Sequence Calcium - metabolism Calmodulin - metabolism Cell Line, Tumor Elongation Factor 2 Kinase - chemistry Elongation Factor 2 Kinase - genetics Elongation Factor 2 Kinase - metabolism Enzyme Activation Enzymology Humans Kinetics Molecular Sequence Data Mutagenesis, Site-Directed Phosphorylation Protein Biosynthesis Sequence Homology, Amino Acid Substrate Specificity Threonine - metabolism |
| Title | The Molecular Mechanism of Eukaryotic Elongation Factor 2 Kinase Activation |
| URI | https://dx.doi.org/10.1074/jbc.M114.577148 https://www.ncbi.nlm.nih.gov/pubmed/25012662 https://www.proquest.com/docview/1555627989 https://pubmed.ncbi.nlm.nih.gov/PMC4156036 |
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