TOR mutations confer rapamycin resistance by preventing interaction with FKBP12-rapamycin.

Journal Article (Journal Article)

The antifungal, immunosuppressive compound rapamycin arrests the cell cycle in G1 in both yeast cells and T-lymphocytes. Previous genetic studies in yeast identified mutations in three genes, FPR1 (FKBP12), TOR1, and TOR2, which confer rapamycin resistance, and genetic findings implicated the TOR proteins as direct targets of FKBP12-rapamycin. Consistent with this model, we find that modulating TOR1 and TOR2 expression alters rapamycin sensitivity. We describe several TOR2 mutations that confer rapamycin resistance. These mutations prevent FKBP12-rapamycin binding to TOR2, as assayed with the two-hybrid system. We find that TOR1 and the mammalian TOR homologue (mTOR) also bind FKBP12-rapamycin, and mutations corresponding to those in TOR2 similarly block FKBP12-rapamycin binding. We demonstrate that FKBP12 prolyl isomerase activity is not required for FKBP12-rapamycin binding to TOR and that a composite protein-drug surface contacts the TOR proteins. These studies confirm that the TOR proteins are direct targets of FKBP12-rapamycin, reveal that drug-resistant mutations prevent this association, and define structural features of these complexes.

Full Text

Duke Authors

Cited Authors

  • Lorenz, MC; Heitman, J

Published Date

  • November 17, 1995

Published In

Volume / Issue

  • 270 / 46

Start / End Page

  • 27531 - 27537

PubMed ID

  • 7499212

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.270.46.27531


  • eng

Conference Location

  • United States