Insights into regulation of mTOR signalling through in silico analysis

November 2020 — The mTOR signalling pathway, which is highly conserved from yeast to humans, regulates many important cellular processes that control growth and ageing. A critical key protein in this pathway is mTOR, a kinase that modifies certain proteins by adding a phosphate group to them, a process called phosphorylation. Another protein, DEPTOR, binds to mTOR and is thought to inhibit it, but mTOR in return phosphorylates an extended linker of DEPTOR which leads to the latter's degradation by the proteasome. Using the crystal structure of mTOR, Teh Aik Hong and his group have conceived a model of the mTOR–DEPTOR complex in an attempt to explain the interaction between these two proteins. The model shows a possible spatial arrangement that allows the extended linker of DEPTOR to bind to mTOR's catalytic site. As DEPTOR's degradation requires additional phosphorylation of its linker by another kinase, CK1α, the docking analysis also reveals how mTOR-mediated phosphorylation may facilitate the phosphorylation of DEPTOR by CK1α. These results further suggest that mTOR activation is regulated by yet an unknown mechanism rather than DEPTOR; as the master regulator of cell metabolism, it is unsurprising that mTOR regulation involves mechanisms much more complex than currently known.

https://www.sciencedirect.com/science/article/pii/S1047847720301751