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Projects

Melcher Laboratory

AMPK, a potential target for the treatment of diabetes, obesity and cancer

Cells use ATP to drive energy-consuming cellular processes, such as muscle contraction, cell growth and neuronal excitation. Adenosine-monophosphate (AMP)-activated protein kinase (AMPK) is a three-subunit protein kinase that functions as a sensor of the energy status in human cells. Its kinase activity is triggered by energy stress (i.e., a drop in the ratio of ATP to AMP/ADP), activating ATP-generating pathways and reducing energy-consuming programs.  

To adjust energy balance, AMPK regulates:

  • Almost all cellular metabolic processes (activation of ATP-generating pathways such as glucose and fatty acid uptake and catabolism, and inhibition of energy-consuming pathways such as the synthesis of glycogen, fatty acids, cholesterol, proteins and ribosomal RNA)
  • Whole-body energy balance (appetite regulation in the hypothalamus via leptin, adiponectin, ghrelin and cannabinoids) 
  • Many nonmetabolic processes (cell growth and proliferation, mitochondrial homeostasis, autophagy, aging, neuronal activity and cell polarity)

Due to its central roles in the uptake and metabolism of glucose and fatty acids, AMPK is an important pharmacological target for the treatment of diabetes and obesity. Moreover, AMPK functions context-dependently either as a tumor suppressor or an oncogene, and has therefore also become a potential new target for cancer therapy. We have determined structures of the holo-AMPK complex in different activity states and mechanisms of AMPK activation (Li et al 2015), coordinated adenine nucleotide sensing (Gu et al 2017) and AMPK activation by pharmacological AMPK activators (Gu et al 2017; Gu et al 2018). The long-term goal of this project is to develop an understanding of the different levels of AMPK regulation by direct binding of AMP, ADP, ATP and drugs in order to provide a structural framework for the rational design of new therapeutic AMPK modulators.

Mechanisms of transcriptional and epigenetic regulation in plant stress hormone signaling

Our interest in plant hormone signaling began in 2009, when we determined the structural mechanism by which reception of the plant hormone abscisic acid (ABA) is coupled to inhibition of PP2C protein phosphatases (cover article in Nature, featured as one of the Top 10 Breakthroughs of 2009 by Science and one of the Top 10 Signaling Breakthroughs by Science Signaling). In subsequent work, we identified the structural mechanisms of how PP2Cs inhibit AMPK-related kinases both catalytically and sterically (Soon FF et al 2012), how relief of inhibition allows kinase autoactivation (Ng et al 2011), and the mechanism of receptor antagonism (Melcher et al 2010).

Following our work on ABA, we have analyzed the signaling mechanisms of two other stress hormones — strigolactones (Jiang et al 2013; Zhao L et al 2013; Zhao L et al 2015) and jasmonates (Zhang et al 2015; Ke et al 2015; Feng et al 2017; Ma et al 2017). The latter work focuses on repression of plant MYC transcription factors, which is an active project in the lab that serves as a paradigm for transcriptional and epigenetic mechanisms of gene regulation across species.

Mechanisms of transcriptional and epigenetic regulation in plant stress hormone signaling

WNT signaling is essential for embryonic development and stem cell maintenance, and dysregulation of WNT signaling is associated with numerous cancers, as well as neurodegenerative, bone, and eye diseases. Targeting the WNT pathway is therefore of great therapeutic interest and is intensely pursued. WNTs are palmitoylated and glycosylated morphogens that bind Frizzled (FZD) receptors and different coreceptors, of which the LRP5/LRP6 coreceptors are essential for canonical/β-catenin-mediated WNT signaling. While the intracellular signal transduction pathway is relatively well understood, in the absence of a WNT-FZD-LRP structure it remains unknown how WNT binding to its receptor/coreceptor complexes leads to signaling across the membrane, knowledge that is a key to the development of Frizzled-selective therapeutics. We have used both WNT and the atypical WNT receptor agonist Norrin as model to study receptor activation (Ke et al 2013; Shen et al 2015; DeBruine et al 2017; Yang et al 2018), an area that we continue to actively pursue.