Peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP12 F36V mutant) (FKBP12 F36V)

FKBP12 F36V is an engineered variant of the human Peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP12), where the phenylalanine at position 36 is replaced by a valine residue (Clackson et al., 1998). This specific mutation creates a unique hydrophobic pocket, or "hole," in the protein's binding site that accommodates "bumped" synthetic ligands with high specificity (Nabet et al., 2018). These ligands, such as AP1867 or Shield-1, are designed to bind the mutant protein with high affinity while exhibiting minimal interaction with the wild-type FKBP12 (Banaszynski et al., 2006). This "bump-and-hole" strategy is the foundation of the Degradation TAG (dTAG) system, which enables the rapid and reversible degradation of any protein fused to the FKBP12 F36V tag (Nabet et al., 2018). In this system, a heterobifunctional molecule like dTAG-13 recruits an E3 ubiquitin ligase to the fusion protein, leading to its ubiquitination and proteasomal destruction (Addgene, 2018). Beyond degradation, the mutant is used in "destabilizing domain" (DD) systems to control protein stability and in "suicide switches" for cell therapies (Straathof et al., 2005). For example, the dimerizing drug rimiducid (AP1903) can be used to induce apoptosis in CAR-T cells expressing a caspase-9-FKBP12 F36V fusion (Straathof et al., 2005). Consequently, FKBP12 F36V serves as a critical tool for target validation in drug discovery and a safety mechanism in advanced biologics (Chemical Probes Portal, 2021). The system's ability to provide precise temporal control over protein levels makes it invaluable for studying complex biological pathways. Overall, FKBP12 F36V is a versatile engineered target that bridges chemical biology and therapeutic development.

Other names

FKBP12 F36VFKBP12(F36V)FKBPVF36V-FKBPFKBP1A F36VdTAGFK506-binding protein 12 (F36V mutant)

Induced proximity, targeted protein degradation, protein stabilization, and dimerization.