RAFT1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs
Abstract
The immunosuppressants rapamycin and FK506 bind to the same intracellular protein, the immunophilin FKBP12. The FKB12-FK506 complex interacts with and inhibits the Ca(2+)-activated protein phosphatase calcineurin. The target of the FKBP12-rapamycin complex has not yet been identified. We report that a protein complex containing 245 kDa and 35 kDa components, designated rapamycin and FKBP12 targets 1 and 2 (RAFT1 and RAFT2), interacts with FKBP12 in a rapamycin-dependent manner. Sequences (330 amino acids total) of tryptic peptides derived from the 245 kDa RAFT1 reveal striking homologies to the yeast TOR gene products, which were originally identified by mutations that confer rapamycin resistance in yeast. A RAFT1 cDNA was obtained and found to encode a 289 kDa protein (2549 amino acids) that is 43% and 39% identical to TOR2 and TOR1, respectively. We propose that RAFT1 is the direct target of FKBP12-rapamycin and a mammalian homolog of the TOR proteins.
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These natural products remodeled their target proteins (immunophilins), recruiting novel interacting proteins to form entirely new ternary complexes.
“their combined research revealed that these natural products remodeled their target proteins, a group of proteins named the immunophilins, recruiting novel interacting proteins to form entirely new ternary complexes (liu et al. 1991;Brown et al. 1994;Sabatini et al. 1994).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Sabatini et al. 1994
FK506 and rapamycin bind FKPB12, and these binary complexes induce inhibitory interactions with calcineurin and FRAP/mTOR, respectively.
“The former two bind to FKPB12 and these binary complexes induce inhibitory interactions with calcineurin and FRAP (later mTOR, mammalian Target of Rapamycin), respectively.78,79”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [79]
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Molecular glues and bifunctional compounds: Therapeutic modalities based on induced proximity
Schreiber, S. L. (2024) · Cell Chemical Biology · doi:10.1016/j.chembiol.2024.05.004 · Cited by 112 · see citing works
Effects of exercise on cellular and tissue aging
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Signal-transduction cascades as targets for therapeutic intervention by natural products
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“…the kinase mtOR, respectively, explaining the immunosuppressant behavior of these natural products (Schreiber and crabtree 1992; Brown et al. 1994; Sabatini et al. 1994). their race – remembered in a recent review by Schreiber (Schreiber 2021) – brought about the new field of induced proximity…”
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The mTOR pathway: a common link between Alzheimer's disease and Down Syndrome
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- Authors
- Sabatini, D. M., Erdjument-Bromage, H., Lui, M., Tempst, P., & Snyder, S. H.
- Affiliations
- Johns Hopkins University (US)
- Memorial Sloan Kettering Cancer Center (US)
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 1994-07
- Volume
- 78
- Issue
- 1
- Pages
- 35-43
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2114859236
- Cited by
- 1,509
- References
- 57
- Citations by year
- 2026: 20 · 2025: 27 · 2024: 48 · 2023: 45 · 2022: 52 · 2021: 65 · 2020: 59 · 2019: 60 · 2018: 61 · 2017: 51 · 2016: 52 · 2015: 63 · 2014: 61 · 2013: 53 · 2012: 47
- FWCI
- 23.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Drug Abuse (DA 00074, DA.00266)
- National Institute of General Medical Sciences (T32GM007309, GM07309)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- FKBP12, rapamycin, TOR1, TOR2, FK506, immunophilins, protein complexes, rapamycin resistance, calcineurin, immunosuppressants
- MeSH terms
- Amino Acid Sequence, Animals, Base Sequence, Brain Chemistry, Carrier Proteins, Cloning, Molecular, Cross-Linking Reagents, Fungal Proteins, Heat-Shock Proteins, Molecular Sequence Data, Polyenes, Saccharomyces cerevisiae, Succinimides, Sequence Alignment, Tacrolimus, Sequence Homology, Amino Acid, Sequence Analysis, Phosphotransferases (Alcohol Group Acceptor), DNA, Complementary, Cell Cycle Proteins, Phosphatidylinositol 3-Kinases, Sirolimus, Tacrolimus Binding Proteins, Saccharomyces cerevisiae Proteins, Rats, TOR Serine-Threonine Kinases
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