Peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP-12) (FKBP12)

Peptidyl-prolyl cis-trans isomerase FKBP1A, commonly known as FKBP-12, is a ubiquitous cytosolic protein that belongs to the immunophilin family [UniProt: P62942]. It possesses intrinsic enzymatic activity, facilitating the folding of proteins containing proline residues, and plays a role in modulating intracellular calcium release through interactions with ryanodine receptors [PubMed: 17041062]. In a pharmacological context, FKBP-12 serves as the primary intracellular receptor for the macrolide drug rapamycin (sirolimus) and its derivatives [StatPearls: Sirolimus]. The binding of rapamycin to FKBP-12 creates a gain-of-function complex that physically interacts with the FKBP-rapamycin binding (FRB) domain of the mechanistic target of rapamycin (mTOR) [PMID: 7526102]. This specific interaction results in the allosteric inhibition of mTOR Complex 1 (mTORC1), thereby suppressing downstream signaling pathways essential for cell growth, protein synthesis, and cell cycle progression [PubMed: 22566325]. This mechanism is therapeutically exploited to prevent organ transplant rejection and to treat various cancers and hamartoma syndromes characterized by hyperactive mTOR signaling [NCI Drug Dictionary].

Other names

FK506-binding protein 1AFKBP1FKBP-12PPIase FKBP1A12 kDa FK506-binding proteinImmunophilin FKBP12

Drugs like sirolimus bind to FKBP-12 to form a gain-of-function complex that allosterically inhibits the mechanistic target of rapamycin complex 1 (mTORC1) by binding to the FRB domain of the mTOR kinase, sterically hindering substrate access [PMID: 7526102].