The DOI matches its Crossref record; 7 of the 7 references it cites were found in a registry or an index.
TOR Mutations Confer Rapamycin Resistance by Preventing Interaction with FKBP12-Rapamycin
Open accessAbstract
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.
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Cites
Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes
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The mechanism of action of cyclosporin A and FK506
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Isolation of a Protein Target of the FKBP12-Rapamycin Complex in Mammalian Cells
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RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex.
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Cited by
Loewith, R., Jacinto, E., Wullschleger, S., Lorberg, A., Crespo, J. L., Bonenfant, D., Oppliger, W., Jenoe, P., & Hall, M. N. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00636-6 · Cited by 1,886
Regulation of translation initiation by FRAP/mTOR
Gingras, A.-C., Raught, B., & Sonenberg, N. (2001) · Genes & Development · doi:10.1101/gad.887201 · Cited by 1,545
Tor, a Phosphatidylinositol Kinase Homologue, Controls Autophagy in Yeast
Noda, T., & Ohsumi, Y. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.7.3963 · Cited by 1,309
Structure of the FKBP12-Rapamycin Complex Interacting with Binding Domain of Human FRAP
Choi, J., Chen, J., Schreiber, S. L., & Clardy, J. (1996) · Science · doi:10.1126/science.273.5272.239 · Cited by 929
Target of Rapamycin (TOR) in Nutrient Signaling and Growth Control
Loewith, R., & Hall, M. N. (2011) · Genetics · doi:10.1534/genetics.111.133363 · Cited by 910
Metadata
- Authors
- Lorenz, M. C., & Heitman, J.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1995-11
- Volume
- 270
- Issue
- 46
- Pages
- 27531-27537
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1991691392
- Cited by
- 238
- References
- 7
- FWCI
- 2.13
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Lorenz, M. C., & Heitman, J. (1995). TOR Mutations Confer Rapamycin Resistance by Preventing Interaction with FKBP12-Rapamycin. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.270.46.27531
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Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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