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Crystal structure of the heterotrimer core of Saccharomyces cerevisiae AMPK homologue SNF1

Nature volume 449, pages 492–495 (2007)Cite this article

Abstract

AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis in mammals and is an attractive target for drug discovery against diabetes, obesity and other diseases1,2,3,4,5. The AMPK homologue in Saccharomyces cerevisiae, known as SNF1, is essential for responses to glucose starvation as well as for other cellular processes, although SNF1 seems to be activated by a ligand other than AMP1,6,7,8. Here we report the crystal structure at 2.6 Å resolution of the heterotrimer core of SNF1. The ligand-binding site in the γ-subunit (Snf4) has clear structural differences from that of the Schizosaccharomyces pombe enzyme9, although our crystallographic data indicate that AMP can also bind to Snf4. The glycogen-binding domain in the β-subunit (Sip2) interacts with Snf4 in the heterotrimer but should still be able to bind carbohydrates10,11,12,13. Our structure is supported by a large body of biochemical and genetic data on this complex1,6,7,8,14,15,16,17,18. Most significantly, the structure reveals that part of the regulatory sequence in the α-subunit (Snf1)15,16,18,19 is sequestered by Snf4, demonstrating a direct interaction between the α- and γ-subunits and indicating that our structure may represent the heterotrimer core of SNF1 in its activated state.

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Figure 1: Structure of the heterotrimer core of S. cerevisiae SNF1.
Figure 2: Large conformational differences for the Bateman2 domain of Snf4.
Figure 3: Structure of the ligand-binding site in S. cerevisiae Snf4.

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Acknowledgements

We thank M. Carlson for helpful discussions; H. Robinson and N. Whalen for setting up the X29A beamline; and J. Schwanof and R. Abramowitz for setting up the X4C beamline at the National Synchrotron Light Source. This research is supported in part by an NIH grant to L.T. G.A.A. was supported by an NIH training program in molecular biophysics.

The atomic coordinates are deposited at the Protein Data Bank under accession number 2QLV.

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  1. Gabriele A. Amodeo and Michael J. Rudolph: These authors contributed equally to this work.

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  1. Department of Biological Sciences, Columbia University, New York, New York 10027, USA,

    Gabriele A. Amodeo, Michael J. Rudolph & Liang Tong

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Correspondence to Liang Tong.

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The file contains a more detailed Supplementary Methods section with additional references, Supplementary Table1 and Supplementary Figures 1-9 with Legends. (PDF 3690 kb)

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Amodeo, G., Rudolph, M. & Tong, L. Crystal structure of the heterotrimer core of Saccharomyces cerevisiae AMPK homologue SNF1. Nature 449, 492–495 (2007). https://doi.org/10.1038/nature06127

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