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Regulation of AMP‐activated protein kinase by a pseudosubstrate sequence on the γ subunit
Author(s) -
Scott John W,
Ross Fiona A,
Liu JK David,
Hardie D Grahame
Publication year - 2007
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601542
Subject(s) - biology , protein subunit , protein kinase a , sequence (biology) , microbiology and biotechnology , biochemistry , kinase , gene
The AMP‐activated protein kinase (AMPK) system monitors cellular energy status by sensing AMP and ATP, and is a key regulator of energy balance at the cellular and whole‐body levels. AMPK exists as heterotrimeric αβγ complexes, and the γ subunits contain two tandem domains that bind the regulatory nucleotides. There is a sequence in the first of these domains that is conserved in γ subunit homologues in all eukaryotes, and which resembles the sequence around sites phosphorylated on target proteins of AMPK, except that it has a non‐phosphorylatable residue in place of serine. We propose that in the absence of AMP this pseudosubstrate sequence binds to the active site groove on the α subunit, preventing phosphorylation by the upstream kinase, LKB1, and access to downstream targets. Binding of AMP causes a conformational change that prevents this interaction and relieves the inhibition. We present several lines of evidence supporting this hypothesis.