CRTC1 interacts with MYC as a biomarker of cancers

Type- A amino butyric acid receptors (GABARs) are the major players of rapid inhibitory synaptic transmission in the human brain. These receptors belong to a superfamily of pentameric ligand-gated ion channels known as the Cys-loop receptors. A decrease in GABAR signaling drives hyperactive neurological disorders such as insomnia, anxiety and epilepsy. Here, we report the first X-ray structure of a GABAR, the human b3 homo pentamer, co-crystallized with a novel agonist, benzamidine.

Firstly, we found that the neurotransmitter-binding pocket of GABARs is located between ECDs. As benzamidine is known as a highly potent serine-protease inhibitor, derivatives of which are in clinical trials for prevention of blood clotting. The benzamidine benzyl ring is stacked between the side chains of Phe 200 and Tyr 62, where as its amidinium group forms hydrogen bonds with the Glu 155 side chain.

However, given thatGABARb3 agonists such as histamine act instead as potentiators of heteromeric GABARs, characterization of benzamidine derivatives as positive modulators may offer new opportunities in drug development. At last, we have also identified to glycosylation site in GABAR.

This work provides a rational basis for understanding how multiple human disease mutations affect GABAR assembly, glycosylation and agonist binding, as well as the signal transduction and gating processes.

In response to hormone and stress, the cAMP response element binding protein (CREB)-regulated transcriptional coactivator 1 (CRTC1) is assembled. The C1/M2 oncoprotein induces abnormal expression of CREB and NOTCH target genes. Here we report a gain-of-function activity of the C1/M2 oncoprotein that directs its interactions with myelocytomatosis oncogene (MYC) proteins and activate MYC transcription targets, including cell growth and metabolism, survival, and tumorigenesis.

Firstly, we used a cell-based functional screen and found that C1/M2 coactivator activated MYC pathway. This was confirmed by co-immunoprecipitation.

Next, we explore the role of CRTC1 and M2 complex in NOTCH pathway. Human tumors have combined activation of MYC and CREB pathways. MYC oncoprotein is overexpressed in over 50% of all cancers. We construct a series of deletions to pull down the interaction partners. This shows that the domain within MAML2 required for interacting with NOTCH, and it is absent in the C1/M2 fusion protein. We also identified genes regulated by C1/M2 with a Dox-inducible transgene system.

This work suggests that protein interaction may also be apparent in other oncoprotein fusions. And that compounds targeting the C1/M2–MYC interaction represent an attractive strategy for the development anticancer therapeutics in tumors harboring the translocation.

Numerologist Warda is hooked on OG-L002 fishing, collecting. And lastly her encouragement comes from socializing along with her companions.