Structure and Dimerization of the Kinase Domain from Yeast Snf1, a Member of the Snf1/AMPK Protein Family

Nayak, Vinod; Zhao, Kehao; Wyce, Anastasia; Schwartz, Marc F.; Lo, Wen; Berger, Shelley L.; Marmorstein, Ronen

doi:10.1016/j.str.2005.12.008

Cited by 66 publications

(70 citation statements)

References 38 publications

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“…S2A). The CIPK23ΔC T190D dimeric structures are similar to that described for the yeast Snf1 kinase domain (38) that has been suggested to represent a physiological inactive form of the kinase as they bury kinase active sites. CIPK23ΔC T190D dimers are further stabilized by a CHAPS molecule, used in the crystallization procedure, and by a disulfide bond between two equivalent Cys192 residues.…”

Section: Resultssupporting

confidence: 53%

Structural basis of the regulatory mechanism of the plant CIPK family of protein kinases controlling ion homeostasis and abiotic stress

Chaves-Sanjuán

Sánchez-Barrena

González-Rubio

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Plant cells have developed specific protective molecular machinery against environmental stresses. The family of CBL-interacting protein kinases (CIPK) and their interacting activators, the calcium sensors calcineurin B-like (CBLs), work together to decode calcium signals elicited by stress situations. The molecular basis of biological activation of CIPKs relies on the calcium-dependent interaction of a self-inhibitory NAF motif with a particular CBL, the phosphorylation of the activation loop by upstream kinases, and the subsequent phosphorylation of the CBL by the CIPK. We present the crystal structures of the NAF-truncated and pseudophosphorylated kinase domains of CIPK23 and CIPK24/SOS2. In addition, we provide biochemical data showing that although CIPK23 is intrinsically inactive and requires an external stimulation, CIPK24/SOS2 displays basal activity. This data correlates well with the observed conformation of the respective activation loops: Although the loop of CIPK23 is folded into a well-ordered structure that blocks the active site access to substrates, the loop of CIPK24/SOS2 protrudes out of the active site and allows catalysis. These structures together with biochemical and biophysical data show that CIPK kinase activity necessarily requires the coordinated releases of the activation loop from the active site and of the NAF motif from the nucleotide-binding site. Taken all together, we postulate the basis for a conserved calciumdependent NAF-mediated regulation of CIPKs and a variable regulation by upstream kinases.signaling | ion transport | abiotic stress C ell perception of extracellular stimuli is followed by a transient variation in cytosolic calcium concentration. Plants have evolved to produce the specific molecular machinery to interpret this primary information and to transmit this signal to the components that organize the cell response (1-4). The plant family of serine/threonine protein kinases PKS or CIPKs (hereinafter CIPKs) and their activators, the calcium-binding proteins SCaBPs or CBLs (hereinafter CBLs) (5, 6) function together in decoding calcium signals caused by different environmental stimuli. Available data suggest a mechanism in which calcium mediates the formation of stable CIPK-CBL complexes that regulate the phosphorylation state and activity of various ion transporters involved in the maintenance of cell ion homeostasis and abiotic stress responses in plants. Among them, the Arabidopsis thaliana CIPK24/SOS2-CBL4/SOS3 complex activates the Na + /H + antiporter SOS1 to maintain intracellular levels of the toxic Na + low under salt stress (7-9), the CIPK11-CBL2 pair regulates the plasma membrane H + -ATPase AHA2 to control the transmembrane pH gradient (10), the CIPK23-CBL1/9 (11, 12) regulates the activity of the K + transporter AKT1 to increase the plant K + uptake capability under limiting K + supply conditions (12, 13), and CIPK23-CBL1 mediates nitrate sensing and uptake by phosphorylation of the nitrate transporter CHL1 (14). Together these findings show that underst...

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Section: Resultssupporting

confidence: 53%

Structural basis of the regulatory mechanism of the plant CIPK family of protein kinases controlling ion homeostasis and abiotic stress

Chaves-Sanjuán

Sánchez-Barrena

González-Rubio

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Many kinases, including AMPK, require activation loop phosphorylation for the conformational switch from inactive to active conformation. The kinase domain of SnRK2.6 adopted an open conformation that resembles that of unphosphorylated, inactive Snf1 (30). In contrast, SnRK2.3 adopted a closed conformation very similar to that found in phosphorylated, active Snf1 (29) (Fig.…”

Section: Snrk2 Kinases Have Basal Phosphorylation-independent Activitymentioning

confidence: 81%

“…S5). In the crystal structures, the nonphosphorylated SnRK2.3 and -2.6 adopted canonical bilobal kinase folds very similar to those of AMPK and the yeast AMPK homolog Snf1 (25,29,30). A standout feature is the well-ordered SnRK2 box, which forms a single α-helix and is packed parallel against the αC-helix in the N-terminal lobe (Fig.…”

Section: Snrk2 Kinases Have Basal Phosphorylation-independent Activitymentioning

confidence: 90%

Structural basis for basal activity and autoactivation of abscisic acid (ABA) signaling SnRK2 kinases

Soon

Zhou

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

150

163

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Abscisic acid (ABA) is an essential hormone that controls plant growth, development, and responses to abiotic stresses. Central for ABA signaling is the ABA-mediated autoactivation of three monomeric Snf1-related kinases (SnRK2.2, -2.3, and -2.6). In the absence of ABA, SnRK2s are kept in an inactive state by forming physical complexes with type 2C protein phosphatases (PP2Cs). Upon relief of this inhibition, SnRK2 kinases can autoactivate through unknown mechanisms. Here, we report the crystal structures of full-length Arabidopsis thaliana SnRK2.3 and SnRK2.6 at 1.9-and 2.3-Å resolution, respectively. The structures, in combination with biochemical studies, reveal a two-step mechanism of intramolecular kinase activation that resembles the intermolecular activation of cyclin-dependent kinases. First, release of inhibition by PP2C allows the SnRK2s to become partially active because of an intramolecular stabilization of the catalytic domain by a conserved helix in the kinase regulatory domain. This stabilization enables SnRK2s to gain full activity by activation loop autophosphorylation. Autophosphorylation is more efficient in SnRK2.6, which has higher stability than SnRK2.3 and has well-structured activation loop phosphate acceptor sites that are positioned next to the catalytic site. Together, these data provide a structural framework that links ABA-mediated release of PP2C inhibition to activation of SnRK2 kinases.

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“…The crystal structures of the isolated catalytic domain of the mammalian ␣2 (PDB ID: 2H6D) and S. cerevisiae ␣ subunit have been solved (PDB ID: 2H6D) (363,420) together with the core ␣␤␥ interacting complex comprising a COOH-terminal fragment of ␤ subunit, the complete ␥1 subunit, and a C-terminal fragment of the ␣ subunit (11,501,556). Broadly speaking, the structures of ϳ73% of the ␣ subunit, 72% of the ␤ subunit, and 100% of the ␥1 structure are now known notwithstanding some regions of disorder in the ␣ and ␤ fragments ( Figs.…”

Section: Subunit Structuresmentioning

confidence: 99%

AMPK in Health and Disease

Steinberg¹,

Kemp²

2009

Physiological Reviews

1,440

1,419

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The function and survival of all organisms is dependent on the dynamic control of energy metabolism, when energy demand is matched to energy supply. The AMP-activated protein kinase (AMPK) αβγ heterotrimer has emerged as an important integrator of signals that control energy balance through the regulation of multiple biochemical pathways in all eukaryotes. In this review, we begin with the discovery of the AMPK family and discuss the recent structural studies that have revealed the molecular basis for AMP binding to the enzyme's γ subunit. AMPK's regulation involves autoinhibitory features and phosphorylation of both the catalytic α subunit and the β-targeting subunit. We review the role of AMPK at the cellular level through examination of its many substrates and discuss how it controls cellular energy balance. We look at how AMPK integrates stress responses such as exercise as well as nutrient and hormonal signals to control food intake, energy expenditure, and substrate utilization at the whole body level. Lastly, we review the possible role of AMPK in multiple common diseases and the role of the new age of drugs targeting AMPK signaling.

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Structure and Dimerization of the Kinase Domain from Yeast Snf1, a Member of the Snf1/AMPK Protein Family

Cited by 66 publications

References 38 publications

Structural basis of the regulatory mechanism of the plant CIPK family of protein kinases controlling ion homeostasis and abiotic stress

Structural basis of the regulatory mechanism of the plant CIPK family of protein kinases controlling ion homeostasis and abiotic stress

Structural basis for basal activity and autoactivation of abscisic acid (ABA) signaling SnRK2 kinases

AMPK in Health and Disease

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