Heat shock protein HSP 90-beta also called HSP90beta is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

that in humans is encoded by the ''HSP90AB1''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

Function

HSP90AB1 is a

molecular chaperone 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 ass ...

. Chaperones are proteins that bind to other proteins, thereby stabilizing them in an ATP-dependent manner. 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

organelle In cell biology, an organelle is a specialized subunit, usually within a cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as organs are to the body, hence ''organelle,'' th ...

Classification

Human HSPs are classified into 5 major groups according to the HGNC: *

HSP70 The 70 kilodalton heat shock proteins (Hsp70s or DnaK) 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 import ...

* DnaJ (HSP40) * HSPB (small heat shock proteins) * HSPC (HSP90) *

chaperonin HSP60, also known as chaperonins (Cpn), is a family of heat shock proteins originally sorted by their 60kDa molecular mass. They prevent misfolding of proteins during stressful situations such as high heat, by assisting protein folding. HSP60 bel ...

s 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: * 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. For example, the co-chaperone CDC37 (cell division cycle 37) stabilizes the cell cycle regulatory proteins

CDK4 Cyclin-dependent kinase 4 also known as cell division protein kinase 4 is an enzyme that in humans is encoded by the ''CDK4'' gene. CDK4 is a member of the cyclin-dependent kinase family. Function The protein encoded by this gene is a member o ...

(cyclin dependent kinase 4) and Cdk6. Hop (HSP organizing protein) mediates the interaction between different HSPs, forming

– HSP90 complexes. TOM70 (translocase of the outer mitochondrial membrane of ~70 kDa) mediates translocation of client proteins through the import pore into the mitochondrial matrix.

Isoforms

Human HPS90AB1 shares 60% overall homology to its closest relative HSP90AA1. Murine HSP90AB1 was cloned in 1987 based on homology of the corresponding ''

Drosophila melanogaster ''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the " vinegar fly" or "pomace fly". Starting with ...

'' gene.

Protein structure

HSP90AB1 is active as homodimer, forming a V-shaped structure. It consists of three major domains: *

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

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. Inhibition of HSP90 activity by geldanamycin derivatives is based on their binding to the ATP binding site.

Client proteins

Client proteins are steroid hormone receptors,

kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...

ubiquitin ligase A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquit ...

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...

s and proteins from many more families. Examples of HSP90AB1 client proteins are p38MAPK/ MAPK14 (mitogen activated protein kinase 14), ERK5 (extracellular regulated kinase 5), or the checkpoint kinase Wee1.

Clinical significance

Cystic fibrosis Cystic fibrosis (CF) is a rare genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. Ot ...

(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 Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ...

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.

Cancer

HSP90AB1 and its co-chaperones are frequently overexpressed in cancer cells. They are able to stabilize mutant proteins thereby allowing survival and increased proliferation of cancer cells. This renders HSPs potential targets for cancer treatment. In

salivary gland tumor Salivary gland tumours, also known as mucous gland adenomas or neoplasms, are tumours that form in the tissues of salivary glands. The salivary glands are classified as major or minor. The major salivary glands consist of the parotid, submandibul ...

s, expression of HSP90AA1 and HSP90AB1 correlates with malignancy, proliferation and

metastasis Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, the ...

. The same is basically true for lung cancers where a correlation with survival was found.