FKBP5

FK506 binding protein 5, also known as FKBP5, is a protein which in humans is encoded by the FKBP5 gene.^[5]

FKBP5
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1KT0, 3O5D, 3O5E, 3O5F, 3O5G, 3O5I, 3O5J, 3O5K, 3O5L, 3O5M, 3O5O, 3O5P, 3O5Q, 3O5R, 4DRH, 4DRI, 4DRK, 4DRM, 4DRN, 4DRO, 4DRP, 4DRQ, 4JFI, 4JFJ, 4JFK, 4JFL, 4JFM, 4R0X, 4TW6, 4TW7, 4TX0, 4W9O, 4W9P, 4W9Q, 5DIT, 5DIU, 5BXJ, 5DIV
Identifiers
Aliases	FKBP5, AIG6, FKBP51, FKBP54, P54, PPIase, Ptg-10, FK506 binding protein 5, FKBP prolyl isomerase 5
External IDs	OMIM: 602623; MGI: 104670; HomoloGene: 3038; GeneCards: FKBP5; OMA:FKBP5 - orthologs
Gene location (Human) Chr. Chromosome 6 (human)[1] Band 6p21.31 Start 35,573,585 bp[1] End 35,728,583 bp[1]
Gene location (Mouse) Chr. Chromosome 17 (mouse)[2] Band 17 A3.3|17 14.66 cM Start 28,618,068 bp[2] End 28,736,501 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in gastric mucosa pericardium Skeletal muscle tissue of biceps brachii right lung skin of hip skin of thigh gastrocnemius muscle left uterine tube corpus epididymis synovial joint Top expressed in stroma of bone marrow lacrimal gland muscle of thigh secondary oocyte thymus gastrula zygote primary oocyte Gonadal ridge seminal vesicula More reference expression data BioGPS More reference expression data
Gene ontology Molecular function isomerase activity protein binding heat shock protein binding peptidyl-prolyl cis-trans isomerase activity FK506 binding Cellular component extracellular exosome membrane nucleus nucleoplasm cytoplasm cytosol Biological process protein peptidyl-prolyl isomerization chaperone-mediated protein folding protein folding response to bacterium Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2289 14229 Ensembl ENSG00000096060 ENSMUSG00000024222 UniProt Q13451 Q64378 RefSeq (mRNA) NM_004117 NM_001145775 NM_001145776 NM_001145777 NM_010220 RefSeq (protein) NP_001139247 NP_001139248 NP_001139249 NP_004108 NP_034350 Location (UCSC) Chr 6: 35.57 – 35.73 Mb Chr 17: 28.62 – 28.74 Mb PubMed search [3] [4]
Wikidata
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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).^[6]

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.^[6]

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.^[7]

Clinical significance

The FKBP5 gene has been found to have multiple polyadenylation sites^[5] and is statistically associated with a higher rate of depressive disorders.^[8]

Decreased methylation in the promoter of the FKBP5 gene has been observed in blood samples from patients with neurodegenerative diseases.^[9]

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.^[6] Macrocyclic FKBP51-selective ligands are non-immunosuppressive, engage FKBP51 in cells, and block the cellular effect of FKBP51.^[10]

Interactions

FKBP5 has been shown to interact with Heat shock protein 90kDa alpha (cytosolic), member A1.^[11]

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.^[12]

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.^[13]

See also

• FKBP4 - a functional antagonist to FKBP5 at corticoid receptors
• FKBP3 - a DNA binding FKBP^[14]