Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 315 (5819): 1726-1729

Copyright © 2007 by the American Association for the Advancement of Science

Crystal Structures of the Adenylate Sensor from Fission Yeast AMP-Activated Protein Kinase

Robert Townley1, and Lawrence Shapiro1,2,3*

Abstract: The 5'-AMP (adenosine monophosphate)–activated protein kinase (AMPK) coordinates metabolic function with energy availability by responding to changes in intracellular ATP (adenosine triphosphate) and AMP concentrations. Here, we report crystal structures at 2.9 and 2.6 Å resolution for ATP- and AMP-bound forms of a core {alpha}ß{gamma} adenylate-binding domain from the fission yeast AMPK homolog. ATP and AMP bind competitively to a single site in the {gamma} subunit, with their respective phosphate groups positioned near function-impairing mutants. Unexpectedly, ATP binds without counterions, amplifying its electrostatic effects on a critical regulatory region where all three subunits converge.

1 Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
2 Edward S. Harkness Eye Institute, Columbia University, New York, NY 10032, USA.
3 Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USA.

* To whom correspondence should be addressed. E-mail: LSS8{at}

Ligand Binding to the AMP-activated Protein Kinase Active Site Mediates Protection of the Activation Loop from Dephosphorylation.
D. G. Chandrashekarappa, R. R. McCartney, and M. C. Schmidt (2013)
J. Biol. Chem. 288, 89-98
   Abstract »    Full Text »    PDF »
Nutritional Control of Growth and Development in Yeast.
J. R. Broach (2012)
Genetics 192, 73-105
   Abstract »    Full Text »    PDF »
AMPK phosphorylation by Ssp1 is required for proper sexual differentiation in fission yeast.
N. Valbuena and S. Moreno (2012)
J. Cell Sci. 125, 2655-2664
   Abstract »    Full Text »    PDF »
Subunit and Domain Requirements for Adenylate-mediated Protection of Snf1 Kinase Activation Loop from Dephosphorylation.
D. G. Chandrashekarappa, R. R. McCartney, and M. C. Schmidt (2011)
J. Biol. Chem. 286, 44532-44541
   Abstract »    Full Text »    PDF »
Cystathionine {beta}-Synthase (CBS) Domains 1 and 2 Fulfill Different Roles in Ionic Strength Sensing of the ATP-binding Cassette (ABC) Transporter OpuA.
A. Karasawa, G. B. Erkens, R. P.- A. Berntsson, R. Otten, G. K. Schuurman-Wolters, F. A. A. Mulder, and B. Poolman (2011)
J. Biol. Chem. 286, 37280-37291
   Abstract »    Full Text »    PDF »
AMP-activated protein kinase--an energy sensor that regulates all aspects of cell function.
D. G. Hardie (2011)
Genes & Dev. 25, 1895-1908
   Abstract »    Full Text »    PDF »
Glucose Controls Phosphoregulation of Hydroxymethylglutaryl Coenzyme A Reductase through the Protein Phosphatase 2A-related Phosphatase Protein, Ppe1, and Insig in Fission Yeast.
J. S. Burg and P. J. Espenshade (2011)
J. Biol. Chem. 286, 27139-27146
   Abstract »    Full Text »    PDF »
AMPK Is a Direct Adenylate Charge-Regulated Protein Kinase.
J. S. Oakhill, R. Steel, Z.-P. Chen, J. W. Scott, N. Ling, S. Tam, and B. E. Kemp (2011)
Science 332, 1433-1435
   Abstract »    Full Text »    PDF »
Adenosine Monophosphate-Activated Protein Kinase: A Central Regulator of Metabolism with Roles in Diabetes, Cancer, and Viral Infection.
D. G. Hardie (2011)
Cold Spring Harb Symp Quant Biol 76, 155-164
   Abstract »    Full Text »    PDF »
Nucleotide-induced conformational transitions in the CBS domain protein MJ0729 of Methanocaldococcus jannaschii.
L. A. Martinez-Cruz, J. A. Encinar, P. Sevilla, I. Oyenarte, I. Gomez-Garcia, D. Aguado-Llera, F. Garcia-Blanco, J. Gomez, and J. L. Neira (2011)
Protein Eng. Des. Sel. 24, 161-169
   Abstract »    Full Text »    PDF »
Whole Body Deletion of AMP-activated Protein Kinase {beta}2 Reduces Muscle AMPK Activity and Exercise Capacity.
G. R. Steinberg, H. M. O'Neill, N. L. Dzamko, S. Galic, T. Naim, R. Koopman, S. B. Jorgensen, J. Honeyman, K. Hewitt, Z.-P. Chen, et al. (2010)
J. Biol. Chem. 285, 37198-37209
   Abstract »    Full Text »    PDF »
{beta}-Subunit myristoylation is the gatekeeper for initiating metabolic stress sensing by AMP-activated protein kinase (AMPK).
J. S. Oakhill, Z.-P. Chen, J. W. Scott, R. Steel, L. A. Castelli, N. Ling, S. L. Macaulay, and B. E. Kemp (2010)
PNAS 107, 19237-19241
   Abstract »    Full Text »    PDF »
Structure and function of polarity-inducing kinase family MARK/Par-1 within the branch of AMPK/Snf1-related kinases.
A. Marx, C. Nugoor, S. Panneerselvam, and E. Mandelkow (2010)
FASEB J 24, 1637-1648
   Abstract »    Full Text »    PDF »
AMPK {beta}1 Deletion Reduces Appetite, Preventing Obesity and Hepatic Insulin Resistance.
N. Dzamko, B. J. W. van Denderen, A. L. Hevener, S. B. Jorgensen, J. Honeyman, S. Galic, Z.-P. Chen, M. J. Watt, D. J. Campbell, G. R. Steinberg, et al. (2010)
J. Biol. Chem. 285, 115-122
   Abstract »    Full Text »    PDF »
Homo-oligomerization and Activation of AMP-activated Protein Kinase Are Mediated by the Kinase Domain {alpha}G-Helix.
R. Scholz, M. Suter, T. Weimann, C. Polge, P. V. Konarev, R. F. Thali, R. D. Tuerk, B. Viollet, T. Wallimann, U. Schlattner, et al. (2009)
J. Biol. Chem. 284, 27425-27437
   Abstract »    Full Text »    PDF »
ATP Binding to the C Terminus of the Arabidopsis thaliana Nitrate/Proton Antiporter, AtCLCa, Regulates Nitrate Transport into Plant Vacuoles.
A. De Angeli, O. Moran, S. Wege, S. Filleur, G. Ephritikhine, S. Thomine, H. Barbier-Brygoo, and F. Gambale (2009)
J. Biol. Chem. 284, 26526-26532
   Abstract »    Full Text »    PDF »
AMPK in Health and Disease.
G. R. Steinberg and B. E. Kemp (2009)
Physiol Rev 89, 1025-1078
   Abstract »    Full Text »    PDF »
A Regulatory Role of the Bateman Domain of IMP Dehydrogenase in Adenylate Nucleotide Biosynthesis.
M. Pimkin, J. Pimkina, and G. D. Markham (2009)
J. Biol. Chem. 284, 7960-7969
   Abstract »    Full Text »    PDF »
Roles of the Glycogen-binding Domain and Snf4 in Glucose Inhibition of SNF1 Protein Kinase.
M. Momcilovic, S. H. Iram, Y. Liu, and M. Carlson (2008)
J. Biol. Chem. 283, 19521-19529
   Abstract »    Full Text »    PDF »
U. Riek, R. Scholz, P. Konarev, A. Rufer, M. Suter, A. Nazabal, P. Ringler, M. Chami, S. A. Muller, D. Neumann, et al. (2008)
J. Biol. Chem. 283, 18331-18343
   Abstract »    Full Text »    PDF »
Downregulation of AMP-activated protein kinase by Cidea-mediated ubiquitination and degradation in brown adipose tissue.
J. Qi, J. Gong, T. Zhao, J. Zhao, P. Lam, J. Ye, J. Z. Li, J. Wu, H.-M. Zhou, and P. Li (2008)
EMBO J. 27, 1537-1548
   Abstract »    Full Text »    PDF »
AMP-activated Protein Kinase Subunit Interactions: {beta}1:{gamma}1 ASSOCIATION REQUIRES {beta}1 Thr-263 AND Tyr-267.
T. J. Iseli, J. S. Oakhill, M. F. Bailey, S. Wee, M. Walter, B. J. van Denderen, L. A. Castelli, F. Katsis, L. A. Witters, D. Stapleton, et al. (2008)
J. Biol. Chem. 283, 4799-4807
   Abstract »    Full Text »    PDF »
5'-AMP-Activated Protein Kinase Signaling in Caenorhabditis elegans.
E. G. Beale (2008)
Experimental Biology and Medicine 233, 12-20
   Abstract »    Full Text »    PDF »
Defining the Mechanism of Activation of AMP-activated Protein Kinase by the Small Molecule A-769662, a Member of the Thienopyridone Family.
M. J. Sanders, Z. S. Ali, B. D. Hegarty, R. Heath, M. A. Snowden, and D. Carling (2007)
J. Biol. Chem. 282, 32539-32548
   Abstract »    Full Text »    PDF »
Inhibition of Skeletal Muscle ClC-1 Chloride Channels by Low Intracellular pH and ATP.
B. Bennetts, M. W. Parker, and B. A. Cromer (2007)
J. Biol. Chem. 282, 32780-32791
   Abstract »    Full Text »    PDF »
A Conserved Sequence Immediately N-terminal to the Bateman Domains in AMP-activated Protein Kinase {gamma} Subunits Is Required for the Interaction with the beta Subunits.
R. Viana, M. C. Towler, D. A. Pan, D. Carling, B. Viollet, D. G. Hardie, and P. Sanz (2007)
J. Biol. Chem. 282, 16117-16125
   Abstract »    Full Text »    PDF »
BIOCHEMISTRY: Balancing Cellular Energy.
D. G. Hardie (2007)
Science 315, 1671-1672
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882