Heat shock protein HSP 90-beta also called HSP90beta is a protein that in humans is encoded by the HSP90AB1 gene. [5] [6] [7]
Heat shock protein HSP 90-beta also called HSP90beta is a protein that in humans is encoded by the HSP90AB1 gene. [5] [6] [7]
HSP90AB1 is a molecular chaperone. Chaperones are proteins that bind to other proteins, thereby stabilizing them [8] [9] [10] [11] [12] [13] [14] in an ATP-dependent manner. [15] 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.
Human HSPs are classified into 5 major groups according to the HGNC: [16] [17]
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: [17] [18]
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 bind to HSPs and influence their activity, substrate (client) specificity and interaction with other HSPs. [14] For example, the co-chaperone CDC37 (cell division cycle 37) stabilizes the cell cycle regulatory proteins CDK4 (cyclin dependent kinase 4) and Cdk6. [19] Hop (HSP organizing protein) mediates the interaction between different HSPs, forming HSP70–HSP90 complexes. [20] [21] TOM70 (translocase of the outer mitochondrial membrane of ~70 kDa) mediates translocation of client proteins through the import pore into the mitochondrial matrix. [21] [22]
Human HPS90AB1 shares 60% overall homology to its closest relative HSP90AA1. [23] Murine HSP90AB1 was cloned in 1987 based on homology of the corresponding Drosophila melanogaster gene. [24] [25]
HSP90AB1 is active as homodimer, forming a V-shaped structure. [21] [26] [27] [28] [29] [30] It consists of three major domains:
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. [21] [31] Inhibition of HSP90 activity by geldanamycin derivatives is based on their binding to the ATP binding site. [15]
Client proteins are steroid hormone receptors, kinases, ubiquitin ligases, transcription factors and proteins from many more families. [14] [32] [33] Examples of HSP90AB1 client proteins are p38MAPK/MAPK14 (mitogen activated protein kinase 14), [34] ERK5 (extracellular regulated kinase 5), [35] or the checkpoint kinase Wee1. [36]
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. [37]
HSP90AB1 and its co-chaperones are frequently overexpressed in cancer cells. [38] They are able to stabilize mutant proteins thereby allowing survival and increased proliferation of cancer cells. This renders HSPs potential targets for cancer treatment. [39] [40] [41] In salivary gland tumors, expression of HSP90AA1 and HSP90AB1 correlates with malignancy, proliferation and metastasis. [42] The same is basically true for lung cancers where a correlation with survival was found. [43]
 | The 2015 version of this article was updated by an external expert under a dual publication model. The corresponding academic peer reviewed article was published in Gene and can be cited as: Michael Haase, Guido Fitze (7 September 2015). "HSP90AB1: Helping the good and the bad". Gene . Gene Wiki Review Series. 575 (2 Pt 1): 171–186. doi:10.1016/J.GENE.2015.08.063. ISSN 0378-1119. PMC 5675009 . PMID 26358502. Wikidata Q38584468. |
In molecular biology, molecular chaperones are proteins that assist the conformational folding or unfolding of large proteins or macromolecular protein complexes. There are a number of classes of molecular chaperones, all of which function to assist large proteins in proper protein folding during or after synthesis, and after partial denaturation. Chaperones are also involved in the translocation of proteins for proteolysis.
Heat shock proteins (HSPs) are a family of proteins produced by cells in response to exposure to stressful conditions. They were first described in relation to heat shock, but are now known to also be expressed during other stresses including exposure to cold, UV light and during wound healing or tissue remodeling. Many members of this group perform chaperone functions by stabilizing new proteins to ensure correct folding or by helping to refold proteins that were damaged by the cell stress. This increase in expression is transcriptionally regulated. The dramatic upregulation of the heat shock proteins is a key part of the heat shock response and is induced primarily by heat shock factor (HSF). HSPs are found in virtually all living organisms, from bacteria to humans.
The 70 kilodalton heat shock proteins are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms. Intracellularly localized Hsp70s are an important part of the cell's machinery for protein folding, performing chaperoning functions, and helping to protect cells from the adverse effects of physiological stresses. Additionally, membrane-bound Hsp70s have been identified as a potential target for cancer therapies and their extracellularly localized counterparts have been identified as having both membrane-bound and membrane-free structures.
Hsp90 is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of proteins required for tumor growth, which is why Hsp90 inhibitors are investigated as anti-cancer drugs.
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The heat shock response (HSR) is a cell stress response that increases the number of molecular chaperones to combat the negative effects on proteins caused by stressors such as increased temperatures, oxidative stress, and heavy metals. In a normal cell, proteostasis must be maintained because proteins are the main functional units of the cell. Many proteins take on a defined configuration in a process known as protein folding in order to perform their biological functions. If these structures are altered, critical processes could be affected, leading to cell damage or death. The heat shock response can be employed under stress to induce the expression of heat shock proteins (HSP), many of which are molecular chaperones, that help prevent or reverse protein misfolding and provide an environment for proper folding.
Heat shock 70 kDa protein 8 also known as heat shock cognate 71 kDa protein or Hsc70 or Hsp73 is a heat shock protein that in humans is encoded by the HSPA8 gene on chromosome 11. As a member of the heat shock protein 70 family and a chaperone protein, it facilitates the proper folding of newly translated and misfolded proteins, as well as stabilize or degrade mutant proteins. Its functions contribute to biological processes including signal transduction, apoptosis, autophagy, protein homeostasis, and cell growth and differentiation. It has been associated with an extensive number of cancers, neurodegenerative diseases, cell senescence, and aging.
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