FKBP5

Function

The protein encoded by this gene is a member of the immunophilin protein family, which play a role in immunoregulation and basic cellular processes involving protein folding and trafficking. This encoded protein is a cis-trans prolyl isomerase that binds to the immunosuppressants tacrolimus (FK506) and sirolimus (rapamycin). It is thought to mediate calcineurin inhibition. It also interacts functionally with mature corticoid receptor hetero-complexes (i.e. progesterone-, glucocorticoid-, mineralocorticoid-receptor complexes) along with the 90 kDa heat shock protein and PTGES3 (P23 protein).

As an Hsp90-associated co-chaperone that regulates the responsiveness of steroid hormone receptors, FKBP51 plays an important role in stress endocrinology and glucocorticoid signaling.

Structure

FKBP5 is part of the FKBP protein family and contains several functional domains. It includes an FKBP-type peptidyl-prolyl cis-trans isomerase (PPIase) domain (FK1), an FKBP-like domain (FK2), and a C-terminal region with three tetratricopeptide repeat (TPR) motifs. The FK1 domain has PPIase activity, facilitating protein folding. In contrast, the FK2 domain, while structurally similar to FK1, lacks measurable PPIase activity. Instead, it is thought to play a role in protein-protein interactions, particularly in binding to progesterone receptor, suggesting a scaffolding function. The TPR motifs in the C-terminal region resemble those found in Hsp90 and contribute to molecular interactions.

Clinical significance

The FKBP5 gene has been found to have multiple polyadenylation sites and is statistically associated with a higher rate of depressive disorders.

Decreased methylation in the promoter of the FKBP5 gene has been observed in blood samples from patients with neurodegenerative diseases.

FKBP51 Ligands

As a key player in several diseases like stress-related disorders, chronic pain, and obesity, FKBP51 is an attractive drug target. SAFit2 currently the most best characterized FKBP51 ligand, has shown promising effects in numerous animal models. Macrocyclic FKBP51-selective ligands are non-immunosuppressive, engage FKBP51 in cells, and block the cellular effect of FKBP51.

Interactions

FKBP5 has been shown to interact with Heat shock protein 90kDa alpha (cytosolic), member A1.

Steroid hormone regulation

FKBP5 interacts with three key steroid hormone receptors: the glucocorticoid receptor (GR), progesterone receptor (PR), and androgen receptor (AR). These receptors regulate gene transcription, including FKBP5 expression. Interestingly, FKBP5 inhibits GR and PR activation, creating a negative feedback loop that limits their activity. In contrast, FKBP5 enhances AR signaling, leading to a positive regulatory effect.

AKT phosphorylation

FKBP5 regulates AKT activity by helping AKT interact with PHLPP, which dephosphorylates AKT at Ser473. FKBP5 binds to AKT through its FK1 domain and to PHLPP through its TPR domain, supporting their interaction. Without FKBP51, the interaction between AKT and PHLPP is reduced, leading to higher AKT phosphorylation at Ser473 and increased AKT activity.

References

References

1. "Entrez Gene: FKBP5 FK506 binding protein 5".
2. (January 2019). "The Many Faces of FKBP51". Biomolecules.
3. (21 January 2019). "The Many Faces of FKBP51". Biomolecules.
4. (December 2004). "Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment". Nature Genetics.
5. (March 2021). "Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders". Genome Biology.
6. (June 2021). "Macrocyclic FKBP51 Ligands Define a Transient Binding Mode with Enhanced Selectivity". Angewandte Chemie.
7. (February 1997). "Molecular cloning of human FKBP51 and comparisons of immunophilin interactions with Hsp90 and progesterone receptor". Molecular and Cellular Biology.
8. (December 2013). "The role of FKBP5 in mood disorders: action of FKBP5 on steroid hormone receptors leads to questions about its evolutionary importance". CNS & Neurological Disorders Drug Targets.
9. (November 2021). "FKBP51 and the molecular chaperoning of metabolism". Trends in Endocrinology and Metabolism.
10. (April 2016). "Structural basis of nucleic acid recognition by FK506-binding protein 25 (FKBP25), a nuclear immunophilin". Nucleic Acids Research.