Regulation of mTOR by phosphatidic acid

mTORC1, the mammalian target of rapamycin complex 1, is a key regulator of cellular physiology. The lipid metabolite phosphatidic acid (PA) binds to and ac-tivates mTORC1 in response to nutrients and growth factors. We review struc-tural findings and propose a model for PA activation of mTORC1. PA binds to a highly conserved sequence in the alpha 4 helix of the FK506 binding protein 12 (FKBP12)/rapamycin-binding (FRB) domain of mTOR. It is proposed that PA binding to two adjacent positively charged amino acids breaks and shortens the C-terminal region of helix alpha 4. This has profound consequences for both sub-strate binding and the catalytic activity of mTORC1.

Automated summary

mTORC1, a key regulator of cellular physiology, is activated by the lipid metabolite phosphatidic acid (PA). PA binds to a conserved sequence in the alpha 4 helix of mTOR's FKBP12/rapamycin-binding (FRB) domain. This binding disrupts and shortens the C-terminal region of the alpha 4 helix, resulting in significant consequences for substrate binding and catalytic activity of mTORC1.