title: A conserved mechanism of autoinhibition for the AMPK kinase domain: ATP-binding site and catalytic loop refolding as a means of regulation.
abstract: The AMP-activated protein kinase (AMPK) is a highly conserved trimeric protein complex that is responsible for energy homeostasis in eukaryotic cells. Here, a 1.9 A resolution crystal structure of the isolated kinase domain from the alpha2 subunit of human AMPK, the first from a multicellular organism, is presented. This human form adopts a catalytically inactive state with distorted ATP-binding and substrate-binding sites. The ATP site is affected by changes in the base of the activation loop, which has moved into an inhibited DFG-out conformation. The substrate-binding site is disturbed by changes within the AMPKalpha2 catalytic loop that further distort the enzyme from a catalytically active form. Similar structural rearrangements have been observed in a yeast AMPK homologue in response to the binding of its auto-inhibitory domain; restructuring of the kinase catalytic loop is therefore a conserved feature of the AMPK protein family and is likely to represent an inhibitory mechanism that is utilized during function.
authors.affiliation: The Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada. dene@phys.unsw.edu.au
authors.forename: Dene R
authors.initials: DR
authors.lastname: Littler
authors.forename: John R
authors.initials: JR
authors.lastname: Walker
authors.forename: Tara
authors.initials: T
authors.lastname: Davis
authors.forename: Leanne E
authors.initials: LE
authors.lastname: Wybenga-Groot
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Finerty
authors.forename: Elena
authors.initials: E
authors.lastname: Newman
authors.forename: Farell
authors.initials: F
authors.lastname: Mackenzie
authors.forename: Sirano
authors.initials: S
authors.lastname: Dhe-Paganon
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000737:chemistry* / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000737:chemistry* / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D055162:Biocatalysis; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D021122:Protein Subunits; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases