HSP90B1 explained

Heat shock protein 90kDa beta member 1 (HSP90B1), known also as endoplasmin, gp96, grp94, or ERp99, is a chaperone protein that in humans is encoded by the HSP90B1 gene.^{[1] [2]}

HSP90B1 is an HSP90 paralogue that is found in the endoplasmic reticulum. It plays critical roles in folding proteins in the secretory pathway such as Toll-like receptors and integrins.^{[3] [4]} It has been implicated as an essential immune chaperone to regulate both innate and adaptive immunity.^[5] Tumor-derived HSP90B1 (vitespen) has entered clinical trials for cancer immunotherapy.^{[6] [7] [8] [9]}

grp94 has been shown to be a target for treatment of a plethora of diseases such as glaucoma, multiple myeloma, and metastatic cancer. grp94 includes 5 distinct amino acids in its primary sequence which creates 2 unique sub-pockets, S1 and S2. These sub-pockets have been utilized in current research in order to inhibit the chaperone since its client proteins seem to be up-regulated in cancer cells.^[10]

Further reading

• Srivastava P . Interaction of heat shock proteins with peptides and antigen presenting cells: chaperoning of the innate and adaptive immune responses . Annual Review of Immunology . 20 . 1 . 395–425 . 2001 . 11861608 . 10.1146/annurev.immunol.20.100301.064801 .
• Li Z, Dai J, Zheng H, Liu B, Caudill M . An integrated view of the roles and mechanisms of heat shock protein gp96-peptide complex in eliciting immune response . Frontiers in Bioscience . 7 . 4. d731–51 . March 2002 . 11861214 . 10.2741/A808 .
• Dollins DE, Warren JJ, Immormino RM, Gewirth DT . Structures of GRP94-nucleotide complexes reveal mechanistic differences between the hsp90 chaperones . Molecular Cell . 28 . 1 . 41–56 . October 2007 . 17936703 . 2094010 . 10.1016/j.molcel.2007.08.024 .
• Kaul SC, Taira K, Pereira-Smith OM, Wadhwa R . Mortalin: present and prospective . Experimental Gerontology . 37 . 10–11 . 1157–64 . 2003 . 12470827 . 10.1016/S0531-5565(02)00135-3 . 44450296 .
• Schaiff WT, Hruska KA, McCourt DW, Green M, Schwartz BD . HLA-DR associates with specific stress proteins and is retained in the endoplasmic reticulum in invariant chain negative cells . The Journal of Experimental Medicine . 176 . 3 . 657–66 . September 1992 . 1512535 . 2119345 . 10.1084/jem.176.3.657 .
• Zolnierowicz S, Work C, Hutchison K, Fox IH . Partial separation of platelet and placental adenosine receptors from adenosine A2-like binding protein . Molecular Pharmacology . 37 . 4 . 554–9 . April 1990 . 2325637 .
• Hutchison KA, Nevins B, Perini F, Fox IH . Soluble and membrane-associated human low-affinity adenosine binding protein (adenotin): properties and homology with mammalian and avian stress proteins . Biochemistry . 29 . 21 . 5138–44 . May 1990 . 2378869 . 10.1021/bi00473a020 .
• Chang SC, Erwin AE, Lee AS . Glucose-regulated protein (GRP94 and GRP78) genes share common regulatory domains and are coordinately regulated by common trans-acting factors . Molecular and Cellular Biology . 9 . 5 . 2153–62 . May 1989 . 2546060 . 363009 . 10.1128/mcb.9.5.2153.
• Anderson SL, Shen T, Lou J, Xing L, Blachere NE, Srivastava PK, Rubin BY . The endoplasmic reticular heat shock protein gp96 is transcriptionally upregulated in interferon-treated cells . The Journal of Experimental Medicine . 180 . 4 . 1565–9 . October 1994 . 7523574 . 2191700 . 10.1084/jem.180.4.1565 .
• Bruneau N, Lombardo D . Chaperone function of a Grp 94-related protein for folding and transport of the pancreatic bile salt-dependent lipase . The Journal of Biological Chemistry . 270 . 22 . 13524–33 . June 1995 . 7768954 . 10.1074/jbc.270.22.13524 . free .
• Chavany C, Mimnaugh E, Miller P, Bitton R, Nguyen P, Trepel J, Whitesell L, Schnur R, Moyer J, Neckers L . p185erbB2 binds to GRP94 in vivo. Dissociation of the p185erbB2/GRP94 heterocomplex by benzoquinone ansamycins precedes depletion of p185erbB2 . The Journal of Biological Chemistry . 271 . 9 . 4974–7 . March 1996 . 8617772 . 10.1074/jbc.271.9.4974 . free .
• Kuznetsov G, Chen LB, Nigam SK . Multiple molecular chaperones complex with misfolded large oligomeric glycoproteins in the endoplasmic reticulum . The Journal of Biological Chemistry . 272 . 5 . 3057–63 . January 1997 . 9006956 . 10.1074/jbc.272.5.3057 . free .
• Hoshino T, Wang J, Devetten MP, Iwata N, Kajigaya S, Wise RJ, Liu JM, Youssoufian H . Molecular chaperone GRP94 binds to the Fanconi anemia group C protein and regulates its intracellular expression . Blood . 91 . 11 . 4379–86 . June 1998 . 9596688 . 10.1182/blood.v91.11.4379.
• Linnik KM, Herscovitz H . Multiple molecular chaperones interact with apolipoprotein B during its maturation. The network of endoplasmic reticulum-resident chaperones (ERp72, GRP94, calreticulin, and BiP) interacts with apolipoprotein b regardless of its lipidation state . The Journal of Biological Chemistry . 273 . 33 . 21368–73 . August 1998 . 9694898 . 10.1074/jbc.273.33.21368 . free .
• Delom F, Lejeune PJ, Vinet L, Carayon P, Mallet B . Involvement of oxidative reactions and extracellular protein chaperones in the rescue of misassembled thyroglobulin in the follicular lumen . Biochemical and Biophysical Research Communications . 255 . 2 . 438–43 . February 1999 . 10049727 . 10.1006/bbrc.1999.0229 .
• Reddy RK, Lu J, Lee AS . The endoplasmic reticulum chaperone glycoprotein GRP94 with Ca(2+)-binding and antiapoptotic properties is a novel proteolytic target of calpain during etoposide-induced apoptosis . The Journal of Biological Chemistry . 274 . 40 . 28476–83 . October 1999 . 10497210 . 10.1074/jbc.274.40.28476 . free .
• Roher N, Sarno S, Miró F, Ruzzene M, Llorens F, Meggio F, Itarte E, Pinna LA, Plana M . The carboxy-terminal domain of Grp94 binds to protein kinase CK2 alpha but not to CK2 holoenzyme . FEBS Letters . 505 . 1 . 42–6 . September 2001 . 11557039 . 10.1016/S0014-5793(01)02781-8 . 52949128 . free .
• Vabulas RM, Braedel S, Hilf N, Singh-Jasuja H, Herter S, Ahmad-Nejad P, Kirschning CJ, Da Costa C, Rammensee HG, Wagner H, Schild H . The endoplasmic reticulum-resident heat shock protein Gp96 activates dendritic cells via the Toll-like receptor 2/4 pathway . The Journal of Biological Chemistry . 277 . 23 . 20847–53 . June 2002 . 11912201 . 10.1074/jbc.M200425200 . free .
• Shin HJ, Kim SS, Cho YH, Lee SG, Rho HM . Host cell proteins binding to the encapsidation signal epsilon in hepatitis B virus RNA . Archives of Virology . 147 . 3 . 471–91 . March 2002 . 11958450 . 10.1007/s007050200001 . 23653290 . free .

Notes and References

1. Maki RG, Old LJ, Srivastava PK . Human homologue of murine tumor rejection antigen gp96: 5'-regulatory and coding regions and relationship to stress-induced proteins . Proceedings of the National Academy of Sciences of the United States of America . 87 . 15 . 5658–62 . August 1990 . 2377606 . 54386 . 10.1073/pnas.87.15.5658 . 1990PNAS...87.5658M . free .
2. Chen B, Piel WH, Gui L, Bruford E, Monteiro A . The HSP90 family of genes in the human genome: insights into their divergence and evolution . Genomics . 86 . 6 . 627–37 . December 2005 . 16269234 . 10.1016/j.ygeno.2005.08.012 . free .
3. Randow F, Seed B . Endoplasmic reticulum chaperone gp96 is required for innate immunity but not cell viability . Nature Cell Biology . 3 . 10 . 891–6 . October 2001 . 11584270 . 10.1038/ncb1001-891 . 26559580 .
4. Yang Y, Liu B, Dai J, Srivastava PK, Zammit DJ, Lefrançois L, Li Z . Heat shock protein gp96 is a master chaperone for toll-like receptors and is important in the innate function of macrophages . Immunity . 26 . 2 . 215–26 . February 2007 . 17275357 . 2847270 . 10.1016/j.immuni.2006.12.005 .,
5. Schild H, Rammensee HG . gp96--the immune system's Swiss army knife . Nature Immunology . 1 . 2 . 100–1 . August 2000 . 11248798 . 10.1038/77770 . 29571184 .
6. Wood CG, Mulders P . Vitespen: a preclinical and clinical review . Future Oncology . 5 . 6 . 763–74 . August 2009 . 19663726 . 10.2217/fon.09.46 .
7. Tosti G, di Pietro A, Ferrucci PF, Testori A . HSPPC-96 vaccine in metastatic melanoma patients: from the state of the art to a possible future . Expert Review of Vaccines . 8 . 11 . 1513–26 . November 2009 . 19863242 . 10.1586/erv.09.108 . 207223461 .
8. Web site: NCT00293423 . ClinicalTrials.gov, United States National Institutes of Health . GP96 Heat Shock Protein-Peptide Complex Vaccine in Treating Patients With Recurrent or Progressive Glioma . 2010-04-10 .
9. Bloch O, Crane CA, Fuks Y, Kaur R, Aghi MK, Berger MS, Butowski NA, Chang SM, Clarke JL, McDermott MW, Prados MD, Sloan AE, Bruce JN, Parsa AT . Heat-shock protein peptide complex-96 vaccination for recurrent glioblastoma: a phase II, single-arm trial . Neuro-Oncology . 16 . 2 . 274–9 . January 2014 . 24335700 . 10.1093/neuonc/not203 . 3895386 .
10. Khandelwal A, Crowley VM, Blagg BS . Resorcinol-Based Grp94-Selective Inhibitors . EN . ACS Medicinal Chemistry Letters . 8 . 10 . 1013–1018 . October 2017 . 29057043 . 5641966 . 10.1021/acsmedchemlett.7b00193 .