Regulation of mTOR by phosphatidic acid

Trends Endocrinol Metab. 2023 Mar;34(3):170-180. doi: 10.1016/j.tem.2023.01.004. Epub 2023 Jan 31.

Abstract

mTORC1, the mammalian target of rapamycin complex 1, is a key regulator of cellular physiology. The lipid metabolite phosphatidic acid (PA) binds to and activates mTORC1 in response to nutrients and growth factors. We review structural findings and propose a model for PA activation of mTORC1. PA binds to a highly conserved sequence in the α4 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 α4. This has profound consequences for both substrate binding and the catalytic activity of mTORC1.

Keywords: FRB; Rheb; mTOR; phosphatidic acid; phospholipase D; structure.

Publication types

  • Review
  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acids / metabolism
  • Humans
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Phosphatidic Acids* / metabolism
  • TOR Serine-Threonine Kinases* / genetics
  • TOR Serine-Threonine Kinases* / metabolism

Substances

  • Phosphatidic Acids
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Amino Acids
  • MTOR protein, human