Regulation of mTOR by phosphatidic acid

Maria A Frias; Ahmet Hatipoglu; David A Foster

doi:10.1016/j.tem.2023.01.004

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.

Authors

Maria A Frias¹, Ahmet Hatipoglu², David A Foster³

Affiliations

¹ Department of Biology and Health Promotion, St. Francis College, Brooklyn, NY 11201, USA; Department of Biological Sciences, Hunter College of the City University of New York, New York, NY 10065, USA. Electronic address: mfrias@sfc.edu.
² Department of Biological Sciences, Hunter College of the City University of New York, New York, NY 10065, USA; Biochemistry Program, Graduate Center of the City University of New York, New York, NY 10016, USA.
³ Department of Biological Sciences, Hunter College of the City University of New York, New York, NY 10065, USA; Biochemistry Program, Graduate Center of the City University of New York, New York, NY 10016, USA; Biology Program, Graduate Center of the City University of New York, New York, NY 10016, USA; Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA. Electronic address: foster@genectr.hunter.cuny.edu.

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding