FK506-binding protein 1A–mechanistic target of rapamycin complex 1 (FKBP12–mTORC1) (FKBP12–mTORC1)

The FK506-binding protein 1A–mechanistic target of rapamycin complex 1 (FKBP12–mTORC1) is a critical signaling node formed when the immunophilin FKBP12 (encoded by the FKBP1A gene) binds to the mTORC1 complex in the presence of rapamycin or its analogs (rapalogs) [1, 2, 4]. mTORC1 is a multi-protein serine/threonine kinase complex—comprising mTOR, Raptor, mLST8, PRAS40, and DEPTOR—that integrates signals from nutrients, growth factors, and energy status to regulate cell growth, protein synthesis, and autophagy [3]. The binding of the FKBP12-rapalog complex to the FKBP12-rapamycin binding (FRB) domain of mTOR induces an allosteric inhibition of the kinase, primarily affecting the phosphorylation of downstream targets like S6K1 and 4E-BP1 [3, 4]. This complex plays a pivotal role in various pathologies, including cancer, where mTORC1 is often hyperactivated, and in the immune response, where its inhibition leads to immunosuppression [3, 5]. Clinically, targeting this complex with rapalogs is a standard therapy for preventing organ transplant rejection and treating specific malignancies such as renal cell carcinoma and tuberous sclerosis complex-associated tumors [4, 5]. Sources: [1] UniProt P62942; [2] UniProt P42345; [3] Saxton and Sabatini, Cell 2017; [4] Benjamin et al., Nat Rev Drug Discov 2011; [5] DrugBank DB00877.

Other names

FKBP12–mTORC1 complexFKBP1A–mTOR complex 1Rapamycin–FKBP12–mTORC1 complexFKBP12–mTORC1

Allosteric inhibition of mTORC1 kinase activity through the formation of a ternary complex between the drug (rapalog), FKBP12, and the FRB domain of mTOR, which physically blocks substrate access to the active site [3, 4].