FKBP5

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
View/Edit Human View/Edit Mouse

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

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]

References

1. GRCh38: Ensembl release 89: ENSG00000096060 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000024222 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: FKBP5 FK506 binding protein 5".
6. Hähle A, Merz S, Meyners C, Hausch F (January 2019). "The Many Faces of FKBP51". Biomolecules. 9 (1): 35. doi: 10.3390/biom9010035 . PMC   6359276 . PMID   30669684.  This article incorporates textfrom this source, which is available under the CC BY 4.0 license.
7. Hähle A, Merz S, Meyners C, Hausch F (21 January 2019). "The Many Faces of FKBP51". Biomolecules. 9 (1): 35. doi: 10.3390/biom9010035 . PMC   6359276 . PMID   30669684.
8. Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Pütz B, et al. (December 2004). "Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment". Nature Genetics. 36 (12): 1319–25. doi:10.1038/ng1479. PMID   15565110. S2CID   21914515.
9. Nabais MF, Laws SM, Lin T, Vallerga CL, Armstrong NJ, Blair IP, et al. (March 2021). "Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders". Genome Biology. 22 (1): 90. doi: 10.1186/s13059-021-02275-5 . PMC   8004462 . PMID   33771206.
10. Voll AM, Meyners C, Taubert MC, Bajaj T, Heymann T, Merz S, et al. (June 2021). "Macrocyclic FKBP51 Ligands Define a Transient Binding Mode with Enhanced Selectivity". Angewandte Chemie. 60 (24): 13257–13263. doi:10.1002/anie.202017352. PMC   8252719 . PMID   33843131.
11. Nair SC, Rimerman RA, Toran EJ, Chen S, Prapapanich V, Butts RN, et al. (February 1997). "Molecular cloning of human FKBP51 and comparisons of immunophilin interactions with Hsp90 and progesterone receptor". Molecular and Cellular Biology. 17 (2): 594–603. doi:10.1128/MCB.17.2.594. PMC   231784 . PMID   9001212.
12. O'Leary JC, Zhang B, Koren J, Blair L, Dickey CA (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. 12 (8): 1157–1162. ISSN   1996-3181. PMC   4236834 . PMID   24040820.
13. Smedlund KB, Sanchez ER, Hinds TD (November 2021). "FKBP51 and the molecular chaperoning of metabolism". Trends in Endocrinology and Metabolism. 32 (11): 862–874. doi:10.1016/j.tem.2021.08.003. PMC   8516732 . PMID   34481731.
14. Prakash A, Shin J, Rajan S, Yoon HS (April 2016). "Structural basis of nucleic acid recognition by FK506-binding protein 25 (FKBP25), a nuclear immunophilin". Nucleic Acids Research. 44 (6): 2909–2925. doi:10.1093/nar/gkw001. PMC   4824100 . PMID   26762975.

Further reading

• Schiene-Fischer C, Yu C (April 2001). "Receptor accessory folding helper enzymes: the functional role of peptidyl prolyl cis/trans isomerases". FEBS Letters. 495 (1–2): 1–6. Bibcode:2001FEBSL.495....1S. doi: 10.1016/S0014-5793(01)02326-2 . PMID   11322937. S2CID   42263861.
• Baughman G, Wiederrecht GJ, Campbell NF, Martin MM, Bourgeois S (August 1995). "FKBP51, a novel T-cell-specific immunophilin capable of calcineurin inhibition". Molecular and Cellular Biology. 15 (8): 4395–402. doi:10.1128/mcb.15.8.4395. PMC   230679 . PMID   7542743.
• Smith DF, Baggenstoss BA, Marion TN, Rimerman RA (August 1993). "Two FKBP-related proteins are associated with progesterone receptor complexes". The Journal of Biological Chemistry. 268 (24): 18365–71. doi: 10.1016/S0021-9258(17)46853-0 . PMID   7688746.
• Smith DF, Albers MW, Schreiber SL, Leach KL, Deibel MR (November 1993). "FKBP54, a novel FK506-binding protein in avian progesterone receptor complexes and HeLa extracts". The Journal of Biological Chemistry. 268 (32): 24270–3. doi: 10.1016/S0021-9258(20)80520-1 . PMID   7693698.
• Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID   8125298.
• Johnson J, Corbisier R, Stensgard B, Toft D (January 1996). "The involvement of p23, hsp90, and immunophilins in the assembly of progesterone receptor complexes". The Journal of Steroid Biochemistry and Molecular Biology. 56 (1-6 Spec No): 31–7. doi:10.1016/0960-0760(95)00221-9. PMID   8603045. S2CID   24410864.
• Nair SC, Rimerman RA, Toran EJ, Chen S, Prapapanich V, Butts RN, et al. (February 1997). "Molecular cloning of human FKBP51 and comparisons of immunophilin interactions with Hsp90 and progesterone receptor". Molecular and Cellular Biology. 17 (2): 594–603. doi:10.1128/MCB.17.2.594. PMC   231784 . PMID   9001212.
• Baughman G, Wiederrecht GJ, Chang F, Martin MM, Bourgeois S (March 1997). "Tissue distribution and abundance of human FKBP51, and FK506-binding protein that can mediate calcineurin inhibition". Biochemical and Biophysical Research Communications. 232 (2): 437–43. doi:10.1006/bbrc.1997.6307. PMID   9125197.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID   9373149.
• Young JC, Obermann WM, Hartl FU (July 1998). "Specific binding of tetratricopeptide repeat proteins to the C-terminal 12-kDa domain of hsp90". The Journal of Biological Chemistry. 273 (29): 18007–10. doi: 10.1074/jbc.273.29.18007 . PMID   9660753.
• Hartley JL, Temple GF, Brasch MA (November 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC   310948 . PMID   11076863.
• Wiemann S, Weil B, Wellenreuther R, Gassenhuber J, Glassl S, Ansorge W, et al. (March 2001). "Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs". Genome Research. 11 (3): 422–35. doi:10.1101/gr.GR1547R. PMC   311072 . PMID   11230166.
• Pirkl F, Buchner J (May 2001). "Functional analysis of the Hsp90-associated human peptidyl prolyl cis/trans isomerases FKBP51, FKBP52 and Cyp40". Journal of Molecular Biology. 308 (4): 795–806. doi:10.1006/jmbi.2001.4595. PMID   11350175.
• Davies TH, Ning YM, Sánchez ER (February 2002). "A new first step in activation of steroid receptors: hormone-induced switching of FKBP51 and FKBP52 immunophilins". The Journal of Biological Chemistry. 277 (7): 4597–600. doi: 10.1074/jbc.C100531200 . PMID   11751894.
• Giraudier S, Chagraoui H, Komura E, Barnache S, Blanchet B, LeCouedic JP, et al. (October 2002). "Overexpression of FKBP51 in idiopathic myelofibrosis regulates the growth factor independence of megakaryocyte progenitors". Blood. 100 (8): 2932–40. doi: 10.1182/blood-2002-02-0485 . PMID   12351405.
• Sinars CR, Cheung-Flynn J, Rimerman RA, Scammell JG, Smith DF, Clardy J (February 2003). "Structure of the large FK506-binding protein FKBP51, an Hsp90-binding protein and a component of steroid receptor complexes". Proceedings of the National Academy of Sciences of the United States of America. 100 (3): 868–73. Bibcode:2003PNAS..100..868S. doi: 10.1073/pnas.0231020100 . PMC   298693 . PMID   12538866.
• Hubler TR, Denny WB, Valentine DL, Cheung-Flynn J, Smith DF, Scammell JG (June 2003). "The FK506-binding immunophilin FKBP51 is transcriptionally regulated by progestin and attenuates progestin responsiveness". Endocrinology. 144 (6): 2380–7. doi: 10.1210/en.2003-0092 . PMID   12746298.
• Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, et al. (February 2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nature Cell Biology. 6 (2): 97–105. doi:10.1038/ncb1086. PMID   14743216. S2CID   11683986.