PRKAA1 (protein kinase AMP-activated catalytic subunit alpha 1)

Description	AMPK α1 is the catalytic subunit of the heterotrimeric AMPK protein with a length of 548 amino acids. In response to an increase in the AMP/ATP ratio, AMPK gets activated. AMP binds to the non-catalytic gamma subunit of the AMPK protein and induces phosphorylation of Thr-183 (Lizcano et al., 2004). This residue is present in the T-loop region of the catalytic subunit, AMPK α1 (Bright et al., 2009). There are several known AMPK kinases (AMPKKs). STK11 (LKB1), complexed with STRADA and CAB39 (MO25), is the major upstream regulator of the AMPK, which phosphorylates the AMP bound protein (Shackelford and Shaw, 2009). Ca2+/calmodulin-dependent protein kinase kinase β ( CAMKK2 or CaMKKβ) is also known to be an upstream kinase of AMPK (Sundararaman et al., 2016). TGF-beta-activated kinase-1 ( MAP3K7 or TAK1) may also phosphorylate AMPK α or at least play a role in its activation as loss of TAK1 leads to impaired AMPK activation (Xie et al., 2006). The AMPK α1 protein consists of several domains (Figure 1). The N-terminal kinase domain carries out the serine/threonine kinase function. The C-terminus regulatory domain contains an α-RIM sensor loop and a β-subunit interaction domain (Crute et al., 1998). A UBA-like auto-inhibitory domain (AID) is present between the α-RIM sensor loop and the kinase domain. AID is required for allosteric regulation via AMP. Absence of this inhibitory region renders the protein independent of AMP but still requires phosphorylation of the activation loop (Crute et al., 1998).
	Figure 1. Domains of AMPK-α1. (AID: UBA-like Autoinhibitory Domain)
Expression	AMPK α1 is widely expressed across many tissues such as brain, heart, kidney, liver and lung (Stapleton et al., 1996).
Localisation	It is primarily localized in the cytoplasm, and with HUVEC cells it was shown that AMPK α1 localizes exclusively in the cytoskeleton (Pinter et al., 2012).
Function	AMPK α1, in its active form, phosphorylates many downstream proteins. These phosphorylated target proteins of AMPK regulate metabolism, autophagy, cell growth and proliferation, and cell polarity (Hardie, 2011). AMPK exists as an obligate heterotrimer in cells (Mihaylova and Shaw, 2011), and all the functions that will be mentioned in this section are carried out by the α1 subunit in this obligate heterotrimer complex. Cellular Metabolism AMPK is activated when there is energy stress in the cell manifested by an increase in the AMP/ATP ratio. In response to this stress, AMPK activates catabolic pathways while inhibiting anabolic pathways. Glycolysis One of the key catabolic pathways for energy generation, glycolysis, is upregulated through AMPK signalling. In order increase glucose uptake to the cell, AMPK activates (induces translocation, short term response) and increases protein expression (longer term response) of SLC2A1 (GLUT1) and SLC2A4 (GLUT4) (Fryer et al., 2002). Also, 6-phosphofructo-2-kinase ( PFKFB3 or PFK-2) gets phosphorylated and activated by AMPK which enhances glycolysis (Marsin et al., 2000). Glycogen synthesis (anabolic pathway) is inhibited by the phosphorylation of glycogen synthase. Gluconeogenesis Anabolic pathways such as gluconeogenesis that enhance glucose levels are inhibited by repression of transcripts that encode for gluconeogenesis enzymes. CRTC2, coactivator of the cyclic AMP response element-binding protein CREB, gets phosphorylated and inhibited (excluded from the nucleus) by AMPK. This leads to disruption of CREB-CRTC2 complex and inhibition of CREB-dependent gluconeogenesis (Lee et al., 2010). Transcription of mRNAs encoding glucose-6-phosphatase and phosphoenolpyruvate carboxykinase are inhibited via this mechanism. Also, class IIA histones, which can activate the FOXO family of transcription factors via HDAC3 recruitment, gets phosphorylated and excluded from the nucleus. This decrease in activity of FOXO family of transcription factors leads to reduced expression of gluconeogenesis genes (Mihaylova et al., 2011). Lipid Metabolism In AMPK activated cells, fatty acid uptake is increased by translocation of fatty acid translocase, CD36 (FAT), to the cellular membrane (Bonen et al., 2007). Meanwhile, acetyl-CoA carboxylase ( ACACA ACC1), which catalyses the rate-limiting step of fatty acid synthesis (Hofbauer et al., 2014), gets phosphorylated and this phosphorylation inhibits the enzymatic activity of ACC1. Along with CD36 (FAT) translocation to the membrane, ACACB (ACC2) is also inhibited which leads to increased fatty acid uptake into mitochondria due to decreased amounts of malonyl-CoA in the cell (Merrill et al., 1997). Protein Synthesis Synthesis of proteins is an enormous energy consuming process for the cells. MTOR, in its active form, promotes cell proliferation and protein synthesis. Activated AMPK inhibits mTOR via phosphorylation of upstream regulator TSC2 (Huang and Manning, 2008) and its subunit RPTOR (Raptor) (Gwinn et al., 2008). Also, eukaryotic elongation factor 2 ( EEF2) is required for the elongation of translation in eukaryotes. EEF2 kinase gets activated by AMPK which inhibits EEF2 via phosphorylation, resulting in inhibition of protein synthesis (Horman et al., 2002). Autophagy Excess or dysfunctional organelles get "eaten up" by the cell over time, this process is called autophagy and it can give cells the advantage of recycling important nutrients, especially during starvation. It is known that mTORc1 inhibits autophagy via inhibition of ULK1 (Chan, 2009), and AMPK downregulates mTORc1 via phosphorylation of TSC2 and Raptor. This was thought to be the main mechanism by which AMPK activates autophagy. Recently, it was found that initiator of autophagy, the ULK1 protein kinase, directly interacts with AMPK, and gets phosphorylated and activated by AMPK (Roach, 2011). Cell Growth and Proliferation AMPK can act as a metabolic checkpoint via inhibition of cellular growth when energy status in the cell is compromised (Mihaylova and Shaw, 2011). Processes of cellular growth and proliferation require many events to take place in the cell such as protein and lipid synthesis. As mentioned above, AMPK can decrease the synthesis of proteins and subsequently cell proliferation through the inhibition of mTORc1. mTORc1 also controls lipid biosynthesis via a transcription factor named as sterol regulatory element-binding protein-1, SREBF1 (SREBP-1) (Laplante and Sabatini, 2009). SREBP-1 targets lipogenic genes such as ACC (Brown et al., 2007); fatty acid synthase, FASN (Jung et al., 2012); and stearoyl-CoA desaturase 1, SCD (Mauvoisin et al., 2007). mTORc1 inhibition by AMPK along with the previously mentioned inhibition of ACC1 leads to decreased lipid synthesis in the cell. Other than metabolic effects, AMPK also activates checkpoint regulators such as TP53 via inactivation of SIRT1 (Sirtuin 1) (Lee et al., 2012) and phosphorylation at Ser-15 (Jones et al., 2005), as well as CDKN1B (cyclin-dependent kinase inhibitor p27(Kip1)) via phosphorylation at Thr198 (Liang et al., 2007). Cell Polarity LKB1-null and AMPK-null Drosophila models show lethal phenotypes with severe defects in cell polarity and mitosis (Lee at al., 2007). AMPK activation was reported to rescue LKB1-null phenotype while non-muscle myosin regulatory light chain (MRLC) phopshomimetic mutants rescued AMPK-null models (Lee at al., 2007). However, another study reported that in mammalian MDCK cells, AMPK activation did not change phosphorylation of MRLC, rather AFDN (afadin) was identified as AMPK substrate for phosphorylation (Zhang et al., 2011). Activation via AMPK leads to deposition of junction components in the cellular membrane. The microtubule plus-end-tracking protein CLIP1 (CLIP-170) is activated via phosphorylation by AMPK. CLIP-170 phosphorylation is required for microtubule dynamics and the regulation of directional cell migration (Nakano et al., 2010). The same study reported that inhibition of AMPK leads to accumulation of CLIP-170 at microtubule tips and slower tubulin polymerization (Nakano et al., 2010). Thus, AMPK also controls microtubule dynamics through CLIP-170 phosphorylation.
	Figure 2. Functions of AMPK
Homology	AMPK α1, with its kinase and regulatory domains, is a very well conserved protein. Homologs of Human PRKAA1 (AMPK α1)   Gene Name   Organism   NCBI RefSeq   Protein   Length (aa)   PRKAA1   H. sapiens   NP_996790.3   5'-AMP-activated protein kinase catalytic subunit alpha-1   574   PRKAA1    P. troglodytes   XP_009447514.1   5'-AMP-activated protein kinase catalytic subunit alpha-1   574   PRKAA1   M. mulatta   XP_001086410.2   5'-AMP-activated protein kinase catalytic subunit alpha-1   559   PRKAA1   C. lupus   XP_022273603.1   5'-AMP-activated protein kinase catalytic subunit alpha-1   573   PRKAA1   B. taurus   NP_001103272   5'-AMP-activated protein kinase catalytic subunit alpha-1   458   Prkaa1   M. musculus   NP_001013385.3   5'-AMP-activated protein kinase catalytic subunit alpha-1   559   Prkaa1   R. norvegicus   NP_062015.2   5'-AMP-activated protein kinase catalytic subunit alpha-1   559   PRKAA1   G. gallus   NP_001034692.1   5'-AMP-activated protein kinase catalytic subunit alpha-1   560   prkaa1   X. tropicalis   NP_001120434.1   5'-AMP-activated protein kinase catalytic subunit alpha-1   551   prkaa1   D. rerio   NP_001103756.1   5'-AMP-activated protein kinase catalytic subunit alpha-1   573   KIN10   A. thaliana   NP_001118546.1   SNF1 kinase homolog 10   512   KIN11   A. thaliana   NP_974374.1   SNF1 kinase homolog 11   512   Os05g0530500   O. sativa   XP_015639849.1   SNF1-related protein kinase catalytic subunit alpha KIN10   505

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