FKBP4 explained

FK506-binding protein 4 is a protein that in humans is encoded by the FKBP4 gene.^{[1] [2]}

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 FK506 and rapamycin. It has high structural and functional similarity to FK506-binding protein 1A (FKBP1A), but unlike FKBP1A, this protein does not have immunosuppressant activity when complexed with FK506. It interacts with interferon regulatory factor-4 and plays an important role in immunoregulatory gene expression in B and T lymphocytes. This encoded protein is known to associate with phytanoyl-CoA alpha-hydroxylase. It can also associate with two heat shock proteins (hsp90 and hsp70) and thus may play a role in the intracellular trafficking of hetero-oligomeric forms of the steroid hormone receptors. This protein correlates strongly with adeno-associated virus type 2 vectors (AAV) resulting in a significant increase in AAV-mediated transgene expression in human cell lines. Thus this encoded protein is thought to have important implications for the optimal use of AAV vectors in human gene therapy.^[2]

Structure

This protein contains TPR repeats and has a PPlase domain.

Clinical significance

Recent research suggests that FKBP4 may play a role in preventing the Tau protein from turning pathogenic. This may prove significant for the development of new Alzheimer's drugs and for detecting the disease before the onset of clinical symptoms.^[3]

Interactions

FKBP4 has been shown to interact with GLMN.^{[4] [5]}

See also

• Glucocorticoid receptor
• Immunophilins
• FKBP5
• FKBP3 - A DNA binding FKBP. ^[6]

Further reading

• Schiene-Fischer C, Yu C . Receptor accessory folding helper enzymes: the functional role of peptidyl prolyl cis/trans isomerases . FEBS Letters . 495 . 1–2 . 1–6 . April 2001 . 11322937 . 10.1016/S0014-5793(01)02326-2 . 42263861 . free .
• Yem AW, Tomasselli AG, Heinrikson RL, Zurcher-Neely H, Ruff VA, Johnson RA, Deibel MR . The Hsp56 component of steroid receptor complexes binds to immobilized FK506 and shows homology to FKBP-12 and FKBP-13 . The Journal of Biological Chemistry . 267 . 5 . 2868–71 . February 1992 . 10.1016/S0021-9258(19)50664-0 . 1371107 . free .
• Tai PK, Albers MW, Chang H, Faber LE, Schreiber SL . Association of a 59-kilodalton immunophilin with the glucocorticoid receptor complex . Science . 256 . 5061 . 1315–8 . May 1992 . 1376003 . 10.1126/science.1376003 . 1992Sci...256.1315T .
• Wiederrecht G, Hung S, Chan HK, Marcy A, Martin M, Calaycay J, Boulton D, Sigal N, Kincaid RL, Siekierka JJ . Characterization of high molecular weight FK-506 binding activities reveals a novel FK-506-binding protein as well as a protein complex . The Journal of Biological Chemistry . 267 . 30 . 21753–60 . October 1992 . 10.1016/S0021-9258(19)36676-1 . 1383226 . free .
• Sanchez ER, Faber LE, Henzel WJ, Pratt WB . The 56-59-kilodalton protein identified in untransformed steroid receptor complexes is a unique protein that exists in cytosol in a complex with both the 70- and 90-kilodalton heat shock proteins . Biochemistry . 29 . 21 . 5145–52 . May 1990 . 2378870 . 10.1021/bi00473a021 .
• Alnemri ES, Fernandes-Alnemri T, Nelki DS, Dudley K, DuBois GC, Litwack G . Overexpression, characterization, and purification of a recombinant mouse immunophilin FKBP-52 and identification of an associated phosphoprotein . Proceedings of the National Academy of Sciences of the United States of America . 90 . 14 . 6839–43 . July 1993 . 8341706 . 47028 . 10.1073/pnas.90.14.6839 . 1993PNAS...90.6839A . free .
• Chambraud B, Radanyi C, Camonis JH, Shazand K, Rajkowski K, Baulieu EE . FAP48, a new protein that forms specific complexes with both immunophilins FKBP59 and FKBP12. Prevention by the immunosuppressant drugs FK506 and rapamycin . The Journal of Biological Chemistry . 271 . 51 . 32923–9 . December 1996 . 8955134 . 10.1074/jbc.271.51.32923 . free .
• Bruner KL, Derfoul A, Robertson NM, Guerriero G, Fernandes-Alnemri T, Alnemri ES, Litwack G . The unliganded mineralocorticoid receptor is associated with heat shock proteins 70 and 90 and the immunophilin FKBP-52 . Receptors & Signal Transduction . 7 . 2 . 85–98 . 1998 . 9392437 .
• Miyata Y, Chambraud B, Radanyi C, Leclerc J, Lebeau MC, Renoir JM, Shirai R, Catelli MG, Yahara I, Baulieu EE . Phosphorylation of the immunosuppressant FK506-binding protein FKBP52 by casein kinase II: regulation of HSP90-binding activity of FKBP52 . Proceedings of the National Academy of Sciences of the United States of America . 94 . 26 . 14500–5 . December 1997 . 9405642 . 25035 . 10.1073/pnas.94.26.14500 . 1997PNAS...9414500M . free .
• Bermingham NA, Rauf S, Katsanis N, Martin JE, Hunter AJ, Fisher EM . The immunophilin FKBP4 (FKBP52/FKBP59) maps to the distal short arm of human chromosome 12 . Mammalian Genome . 9 . 3 . 268 . March 1998 . 9501323 . 10.1007/s003359900746 . 8388657 .
• Chambraud B, Radanyi C, Camonis JH, Rajkowski K, Schumacher M, Baulieu EE . Immunophilins, Refsum disease, and lupus nephritis: the peroxisomal enzyme phytanoyl-COA alpha-hydroxylase is a new FKBP-associated protein . Proceedings of the National Academy of Sciences of the United States of America . 96 . 5 . 2104–9 . March 1999 . 10051602 . 26744 . 10.1073/pnas.96.5.2104 . 1999PNAS...96.2104C . free .
• Mamane Y, Sharma S, Petropoulos L, Lin R, Hiscott J . Posttranslational regulation of IRF-4 activity by the immunophilin FKBP52 . Immunity . 12 . 2 . 129–40 . February 2000 . 10714679 . 10.1016/S1074-7613(00)80166-1 . free .
• Neye H . Mutation of FKBP associated protein 48 (FAP48) at proline 219 disrupts the interaction with FKBP12 and FKBP52 . Regulatory Peptides . 97 . 2–3 . 147–52 . March 2001 . 11164950 . 10.1016/S0167-0115(00)00206-8 . 20617551 .
• Galigniana MD, Radanyi C, Renoir JM, Housley PR, Pratt WB . Evidence that the peptidylprolyl isomerase domain of the hsp90-binding immunophilin FKBP52 is involved in both dynein interaction and glucocorticoid receptor movement to the nucleus . The Journal of Biological Chemistry . 276 . 18 . 14884–9 . May 2001 . 11278753 . 10.1074/jbc.M010809200 . free .
• Qing K, Hansen J, Weigel-Kelley KA, Tan M, Zhou S, Srivastava A . Adeno-associated virus type 2-mediated gene transfer: role of cellular FKBP52 protein in transgene expression . Journal of Virology . 75 . 19 . 8968–76 . October 2001 . 11533160 . 114465 . 10.1128/JVI.75.19.8968-8976.2001 .
• Guo Y, Guettouche T, Fenna M, Boellmann F, Pratt WB, Toft DO, Smith DF, Voellmy R . Evidence for a mechanism of repression of heat shock factor 1 transcriptional activity by a multichaperone complex . The Journal of Biological Chemistry . 276 . 49 . 45791–9 . December 2001 . 11583998 . 10.1074/jbc.M105931200 . free .
• Davies TH, Ning YM, Sánchez ER . 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 . February 2002 . 11751894 . 10.1074/jbc.C100531200 . free .

Notes and References

1. Peattie DA, Harding MW, Fleming MA, DeCenzo MT, Lippke JA, Livingston DJ, Benasutti M . Expression and characterization of human FKBP52, an immunophilin that associates with the 90-kDa heat shock protein and is a component of steroid receptor complexes . Proceedings of the National Academy of Sciences of the United States of America . 89 . 22 . 10974–8 . November 1992 . 1279700 . 50465 . 10.1073/pnas.89.22.10974 . 1992PNAS...8910974P . free .
2. Web site: Entrez Gene: FKBP4 FK506 binding protein 4, 59kDa.
3. Blair LJ, Baker JD, Sabbagh JJ, Dickey CA . The emerging role of peptidyl-prolyl isomerase chaperones in tau oligomerization, amyloid processing, and Alzheimer's disease . Journal of Neurochemistry . 133 . 1 . 1–13 . April 2015 . 25628064 . 4361273 . 10.1111/jnc.13033 .
4. Chambraud B, Radanyi C, Camonis JH, Shazand K, Rajkowski K, Baulieu EE . FAP48, a new protein that forms specific complexes with both immunophilins FKBP59 and FKBP12. Prevention by the immunosuppressant drugs FK506 and rapamycin . The Journal of Biological Chemistry . 271 . 51 . 32923–9 . December 1996 . 8955134 . 10.1074/jbc.271.51.32923 . free .
5. Neye H . Mutation of FKBP associated protein 48 (FAP48) at proline 219 disrupts the interaction with FKBP12 and FKBP52 . Regulatory Peptides . 97 . 2–3 . 147–52 . March 2001 . 11164950 . 10.1016/S0167-0115(00)00206-8 . 20617551 .
6. Prakash . Ajit . Shin . Joon . Rajan . Sreekanth . Yoon . Ho Sup . 2016-04-07 . Structural basis of nucleic acid recognition by FK506-binding protein 25 (FKBP25), a nuclear immunophilin . Nucleic Acids Research . 44 . 6 . 2909–2925 . 10.1093/nar/gkw001 . 0305-1048 . 4824100 . 26762975.