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Title: Crystal Structure of the Heterotrimer Core of Saccharomyces cerevisiae AMPK Homologue SNF1

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 diseases. 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 AMP. Here we report the crystal structure at 2.6 resolution of the heterotrimer core of SNF1. The ligand-binding site in the {gamma}-subunit (Snf4) has clear structural differences from that of the Schizosaccharomyces pombe enzyme, although our crystallographic data indicate that AMP can also bind to Snf4. The glycogen-binding domain in the {beta}-subunit (Sip2) interacts with Snf4 in the heterotrimer but should still be able to bind carbohydrates. Our structure is supported by a large body of biochemical and genetic data on this complex. Most significantly, the structure reveals that part of the regulatory sequence in the {alpha}-subunit (Snf1) is sequestered by Snf4, demonstrating a direct interaction between the {alpha}- and {gamma}-subunits and indicating that our structure may represent the heterotrimer core of SNF1 in its activated state.

Authors:
; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
959509
Report Number(s):
BNL-82495-2009-JA
TRN: US201016%%653
DOE Contract Number:
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature; Journal Volume: 449
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; CARBOHYDRATES; CRYSTAL STRUCTURE; DISEASES; FASTING; GENETICS; GLUCOSE; HOMEOSTASIS; MAMMALS; METABOLIC DISEASES; PHOSPHOTRANSFERASES; PROTEINS; RESOLUTION; SACCHAROMYCES CEREVISIAE; national synchrotron light source

Citation Formats

Amodeo,G., Rudolph, M., and Tong, L. Crystal Structure of the Heterotrimer Core of Saccharomyces cerevisiae AMPK Homologue SNF1. United States: N. p., 2007. Web. doi:10.1038/nature06127.
Amodeo,G., Rudolph, M., & Tong, L. Crystal Structure of the Heterotrimer Core of Saccharomyces cerevisiae AMPK Homologue SNF1. United States. doi:10.1038/nature06127.
Amodeo,G., Rudolph, M., and Tong, L. Mon . "Crystal Structure of the Heterotrimer Core of Saccharomyces cerevisiae AMPK Homologue SNF1". United States. doi:10.1038/nature06127.
@article{osti_959509,
title = {Crystal Structure of the Heterotrimer Core of Saccharomyces cerevisiae AMPK Homologue SNF1},
author = {Amodeo,G. and Rudolph, M. and Tong, L.},
abstractNote = {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 diseases. 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 AMP. Here we report the crystal structure at 2.6 resolution of the heterotrimer core of SNF1. The ligand-binding site in the {gamma}-subunit (Snf4) has clear structural differences from that of the Schizosaccharomyces pombe enzyme, although our crystallographic data indicate that AMP can also bind to Snf4. The glycogen-binding domain in the {beta}-subunit (Sip2) interacts with Snf4 in the heterotrimer but should still be able to bind carbohydrates. Our structure is supported by a large body of biochemical and genetic data on this complex. Most significantly, the structure reveals that part of the regulatory sequence in the {alpha}-subunit (Snf1) is sequestered by Snf4, demonstrating a direct interaction between the {alpha}- and {gamma}-subunits and indicating that our structure may represent the heterotrimer core of SNF1 in its activated state.},
doi = {10.1038/nature06127},
journal = {Nature},
number = ,
volume = 449,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}