HSP90AB1 explained

Heat shock protein HSP 90-beta also called HSP90beta is a protein that in humans is encoded by the HSP90AB1 gene.^{[1] [2] [3]}

Function

HSP90AB1 is a molecular chaperone. Chaperones are proteins that bind to other proteins, thereby stabilizing them^{[4] [5] [6] [7] [8] [9] [10]} in an ATP-dependent manner.^[11] Chaperones stabilize new proteins during translation, mature proteins which are partially unstable but also proteins that have become partially denatured due to various kinds of cellular stress. In case proper folding or refolding is impossible, HSPs mediate protein degradation. They also have specialized functions, such as intracellular transport into organelles.

Classification

See main article: Heat shock protein. Human HSPs are classified into 5 major groups according to the HGNC:^{[12] [13]}

• HSP70
• DnaJ (HSP40)
• HSPB (small heat shock proteins)
• HSPC (HSP90)
• chaperonins

Chaperonins are characterized by their barrel-shaped structure with binding sites for client proteins inside the barrels.

The human HSP90 group consists of 5 members according to the HGNC:^{[13] [14]}

• HSP90AA1 (heat shock protein 90 kDa alpha, class A, member 1)
• HSP90AA3P (heat shock protein 90 alpha family class A member 3, pseudogene)
• HSP90AB1 (heat shock protein 90 kDa alpha, class B, member 1) (this protein)
• HSP90B1 (heat shock protein 90 kDA beta, member 1)
• TRAP1 (TNF receptor associated protein 1)

Whereas HSP90AA1 and HSP90AB1 are located primarily in the cytoplasm of the cells, HSP90B1 can be found in the endoplasmic reticulum and Trap1 in mitochondria.

Co-chaperones

Co-chaperones bind to HSPs and influence their activity, substrate (client) specificity and interaction with other HSPs.^[10] For example, the co-chaperone CDC37 (cell division cycle 37) stabilizes the cell cycle regulatory proteins CDK4 (cyclin dependent kinase 4) and Cdk6.^[15] Hop (HSP organizing protein) mediates the interaction between different HSPs, forming HSP70–HSP90 complexes.^{[16] [17]} TOM70 (translocase of the outer mitochondrial membrane of ~70 kDa) mediates translocation of client proteins through the import pore into the mitochondrial matrix.^{[17] [18]}

Isoforms

Human HPS90AB1 shares 60% overall homology to its closest relative HSP90AA1.^[19] Murine HSP90AB1 was cloned in 1987 based on homology of the corresponding Drosophila melanogaster gene.^{[20] [21]}

Protein structure

HSP90AB1 is active as homodimer, forming a V-shaped structure.^{[17] [22] [23] [24] [25] [26]} It consists of three major domains:

• N-terminal domain (NTD) containing the ATP binding site
• middle domain, primarily responsible for substrate binding
• C-terminal domain (CTD) which is the dimerization domain (base of the V).

Between these domains, there are short charged domains. Co-chaperones primarily bind to the NTD and CTD. The latter Co-chaperones usually contain a tetratricopeptide repeat (TPR) domain which binds to a MEEVD motif at the C-terminus of the HSP.^{[17] [27]} Inhibition of HSP90 activity by geldanamycin derivatives is based on their binding to the ATP binding site.^[11]

Client proteins

Client proteins are steroid hormone receptors, kinases, ubiquitin ligases, transcription factors and proteins from many more families.^{[10] [28] [29]} Examples of HSP90AB1 client proteins are p38MAPK/MAPK14 (mitogen activated protein kinase 14),^[30] ERK5 (extracellular regulated kinase 5),^[31] or the checkpoint kinase Wee1.^[32]

Clinical significance

Cystic fibrosis (CF, mucoviscidosis) is a genetic disease with increased viscosity of various secretions leading to organ failure of lung, pancreas and other organs. It is caused in nearly all cases by a deletion of phenylalanine 508 of CFTR (cystic fibrosis transmembrane conductance regulator). This mutation causes a maturation defect of this ion channel protein with increased degradation, mediated by HSPs. Deletion of the co-chaperone AHA1 (activator of heat shock 90kDa protein ATPase homolog 1) leads to stabilization of CFTR and opens up a perspective for a new therapy.^[33]

Cancer

HSP90AB1 and its co-chaperones are frequently overexpressed in cancer cells.^[34] They are able to stabilize mutant proteins thereby allowing survival and increased proliferation of cancer cells. This renders HSPs potential targets for cancer treatment.^{[35] [36] [37]} In salivary gland tumors, expression of HSP90AA1 and HSP90AB1 correlates with malignancy, proliferation and metastasis.^[38] The same is basically true for lung cancers where a correlation with survival was found.^[39]

Further reading

• Hoffmann T, Hovemann B . Heat-shock proteins, Hsp84 and Hsp86, of mice and men: two related genes encode formerly identified tumour-specific transplantation antigens . Gene . 74 . 2 . 491–501 . Dec 1988 . 2469626 . 10.1016/0378-1119(88)90182-5 .
• Lees-Miller SP, Anderson CW . Two human 90-kDa heat shock proteins are phosphorylated in vivo at conserved serines that are phosphorylated in vitro by casein kinase II . The Journal of Biological Chemistry . 264 . 5 . 2431–7 . Feb 1989 . 10.1016/S0021-9258(19)81631-9 . 2492519 . free .
• Rebbe NF, Ware J, Bertina RM, Modrich P, Stafford DW . Nucleotide sequence of a cDNA for a member of the human 90-kDa heat-shock protein family . Gene . 53 . 2–3 . 235–45 . 1987 . 3301534 . 10.1016/0378-1119(87)90012-6 .
• Tang PZ, Gannon MJ, Andrew A, Miller D . Evidence for oestrogenic regulation of heat shock protein expression in human endometrium and steroid-responsive cell lines . European Journal of Endocrinology. 133 . 5 . 598–605 . Nov 1995 . 7581991 . 10.1530/eje.0.1330598 .
• Nemoto T, Ohara-Nemoto Y, Ota M, Takagi T, Yokoyama K . Mechanism of dimer formation of the 90-kDa heat-shock protein . European Journal of Biochemistry . 233 . 1 . 1–8 . Oct 1995 . 7588731 . 10.1111/j.1432-1033.1995.001_1.x . free .
• Takahashi I, Tanuma R, Hirata M, Hashimoto K . A cosmid clone at the D6S182 locus on human chromosome 6p12 contains the 90-kDa heat shock protein beta gene (HSP90 beta) . Mammalian Genome . 5 . 2 . 121–2 . Feb 1994 . 8180474 . 10.1007/BF00292342 . 30075426 .
• Ji H, Reid GE, Moritz RL, Eddes JS, Burgess AW, Simpson RJ . A two-dimensional gel database of human colon carcinoma proteins . Electrophoresis . 18 . 3–4 . 605–13 . 1997 . 9150948 . 10.1002/elps.1150180344 . 25454450 .
• Yano M, Naito Z, Yokoyama M, Shiraki Y, Ishiwata T, Inokuchi M, Asano G . Expression of hsp90 and cyclin D1 in human breast cancer . Cancer Letters . 137 . 1 . 45–51 . Mar 1999 . 10376793 . 10.1016/S0304-3835(98)00338-3 .
• Sato S, Fujita N, Tsuruo T . Modulation of Akt kinase activity by binding to Hsp90 . Proceedings of the National Academy of Sciences of the United States of America . 97 . 20 . 10832–7 . Sep 2000 . 10995457 . 27109 . 10.1073/pnas.170276797 . 2000PNAS...9710832S . free .
• Gisler SM, Stagljar I, Traebert M, Bacic D, Biber J, Murer H . Interaction of the type IIa Na/Pi cotransporter with PDZ proteins . The Journal of Biological Chemistry . 276 . 12 . 9206–13 . Mar 2001 . 11099500 . 10.1074/jbc.M008745200 . 35476933 . free .
• Wiemann S, Weil B, Wellenreuther R, Gassenhuber J, Glassl S, Ansorge W, Böcher M, Blöcker H, Bauersachs S, Blum H, Lauber J, Düsterhöft A, Beyer A, Köhrer K, Strack N, Mewes HW, Ottenwälder B, Obermaier B, Tampe J, Heubner D, Wambutt R, Korn B, Klein M, Poustka A . 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 . Mar 2001 . 11230166 . 311072 . 10.1101/gr.GR1547R .
• King FW, Wawrzynow A, Höhfeld J, Zylicz M . Co-chaperones Bag-1, Hop and Hsp40 regulate Hsc70 and Hsp90 interactions with wild-type or mutant p53 . The EMBO Journal . 20 . 22 . 6297–305 . Nov 2001 . 11707401 . 125724 . 10.1093/emboj/20.22.6297 .
• Bouhouche-Chatelier L, Chadli A, Catelli MG . The N-terminal adenosine triphosphate binding domain of Hsp90 is necessary and sufficient for interaction with estrogen receptor . Cell Stress & Chaperones . 6 . 4 . 297–305 . Oct 2001 . 10.1379/1466-1268(2001)006<0297:tntatb>2.0.co;2 . 1 November 2024 . 11795466 . 434412 .
• Sato N, Yamamoto T, Sekine Y, Yumioka T, Junicho A, Fuse H, Matsuda T . Involvement of heat-shock protein 90 in the interleukin-6-mediated signaling pathway through STAT3 . Biochemical and Biophysical Research Communications . 300 . 4 . 847–52 . Jan 2003 . 12559950 . 10.1016/S0006-291X(02)02941-8 . 2115/28121 . 1460250 . free .
• Wu JM, Xiao L, Cheng XK, Cui LX, Wu NH, Shen YF . PKC epsilon is a unique regulator for hsp90 beta gene in heat shock response . The Journal of Biological Chemistry . 278 . 51 . 51143–9 . Dec 2003 . 14532285 . 10.1074/jbc.M305537200 . free.
• Nagaraja GM, Kandpal RP . Chromosome 13q12 encoded Rho GTPase activating protein suppresses growth of breast carcinoma cells, and yeast two-hybrid screen shows its interaction with several proteins . Biochemical and Biophysical Research Communications . 313 . 3 . 654–65 . Jan 2004 . 14697242 . 10.1016/j.bbrc.2003.12.001 .
• Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G . A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway . Nature Cell Biology . 6 . 2 . 97–105 . Feb 2004 . 14743216 . 10.1038/ncb1086 . 11683986 .

Notes and References

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3. Web site: NCBI Gene: HSP90AB1 heat shock protein 90 alpha family class B member 1. 2019-08-30.
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12. Web site: Gene group | HUGO Gene Nomenclature Committee. HUGO Gene Nomenclature Committee (HGNC). 30 August 2019.
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19. Rebbe NF, Ware J, Bertina RM, Modrich P, Stafford DW . Nucleotide sequence of a cDNA for a member of the human 90-kDa heat-shock protein family . Gene . 53 . 2–3 . 235–45 . 1987 . 3301534 . 10.1016/0378-1119(87)90012-6.
20. Moore SK, Kozak C, Robinson EA, Ullrich SJ, Appella E . Cloning and nucleotide sequence of the murine hsp84 cDNA and chromosome assignment of related sequences . Gene . 56 . 1 . 29–40 . 1987 . 2445630 . 10.1016/0378-1119(87)90155-7.
21. Moore SK, Kozak C, Robinson EA, Ullrich SJ, Appella E . Murine 86- and 84-kDa heat shock proteins, cDNA sequences, chromosome assignments, and evolutionary origins . The Journal of Biological Chemistry . 264 . 10 . 5343–51 . Apr 1989 . 10.1016/S0021-9258(18)83551-7 . 2925609 . free .
22. Prodromou C, Roe SM, Piper PW, Pearl LH . A molecular clamp in the crystal structure of the N-terminal domain of the yeast Hsp90 chaperone . Nature Structural Biology . 4 . 6 . 477–82 . Jun 1997 . 9187656 . 10.1038/nsb0697-477. 38764610 .
23. Stebbins CE, Russo AA, Schneider C, Rosen N, Hartl FU, Pavletich NP . Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent . Cell . 89 . 2 . 239–50 . Apr 1997 . 9108479 . 10.1016/s0092-8674(00)80203-2. 5253110 . free .
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