Mechanisms of regulation of SNF1/AMPK/SnRK1 protein kinases

Abstract

The SNF1 (sucrose non-fermenting 1)-related protein kinases 1 (SnRKs1) are the plant orthologs of the budding yeast SNF1 and mammalian AMPK (AMP-activated protein kinase). These evolutionarily conserved kinases are metabolic sensors that undergo activation in response to declining energy levels. Upon activation, SNF1/AMPK/SnRK1 kinases trigger a vast transcriptional and metabolic reprograming that restores energy homeostasis and promotes tolerance to adverse conditions, partly through an induction of catabolic processes and a general repression of anabolism. These kinases typically function as a heterotrimeric complex composed of two regulatory subunits, β and γ, and an α-catalytic subunit, which requires phosphorylation of a conserved activation loop residue for activity. Additionally, SNF1/AMPK/SnRK1 kinases are controlled by multiple mechanisms that have an impact on kinase activity, stability, and/or subcellular localization. Here we will review current knowledge on the regulation of SNF1/AMPK/SnRK1 by upstream components, post-translational modifications, various metabolites, hormones, and others, in an attempt to highlight both the commonalities of these essential eukaryotic kinases and the divergences that have evolved to cope with the particularities of each one of these systems.

Keywords: AMPK; Arabidopsis; SNF1; SnRK1; energy signaling; kinase regulation; stress.

FIGURE 1

Heterotrimeric structure of the SNF1/AMPK/SnRK1 complexes. (A) The α-subunit (in blue) is composed of a catalytic domain (in blue with the T-loop in cyan) and a regulatory domain (in purple-blue) which encompasses an auto-inhibitory sequence (AIS) or an ubiquitin-associated (UBA) domain, and a kinase-associated (KA1) domain for binding the β- and γ-subunits. The γ-subunit (in yellow) is composed of two “Bateman” domains each of them containing two CBS (cystathionine-β-synthase) domains and a β-interacting sequence (βIS). The AMPKγ2 and γ3 bear an N-terminal extension and the plant-specific SnRK1βγ possesses a carbohydrate binding module (CBM). The β-subunit (in red) harbors an ASC (association to the complex) domain, containing the sites of interaction with γ and α, a CBM and an N-terminal extension. The KIS (kinase interacting sequence) domain, traditionally used for designating the region comprising the CBM and the site for interaction with the α-subunit, is no longer used. The plant-specific SnRK1β3 is atypical as it does not possess the CBM or the N-terminal extension. (B) Cartoon representation of the 3D-structure (PDB: 2Y94) of the AMPKα1β2γ1 complex. Asterisks designate parts in (A) that were crystallized. Arrows indicate missing parts (CBM), the T-loop, and the two AMP molecules. (C) 3D-structure model of SnRK1α1β1γ, generated with Swiss-Model using as template the AMPK structure presented in (B). Color code in (B,C) as described in (A).

FIGURE 2

Overview of the regulatory mechanisms controlling SNF1/AMPK/SnRK1 kinases described in this review. Multiple factors regulate SNF1 (blue), AMPK (orange), and SnRK1 (green), some of which are conserved in all eukaryotes (black) or only in mammals and yeast (brown). In cases where a specific subunit is the known target of a particular regulatory mechanism this is indicated with a direct arrow to it, whereas in other cases regulation of the complex as a whole (“complex”) is indicated. Broken lines and full lines designate indirect links and direct connections, respectively. P, phosphorylation; Ac, acetylation; Ub, ubiquitination; Ub^K63, ubiquitination through K63 chains; SUMO, small ubiquitin-like modifier; Myr, myristoylation; HS, reduced cysteine; Trx1, thioredoxin1.