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397  structures 7141  species 11  interactions 129386  sequences 5116  architectures

Family: HATPase_c (PF02518)

Summary: Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "GHKL domain". More...

GHKL domain Edit Wikipedia article

Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase
PDB 1ah6 EBI.jpg
Structure of the N-terminal domain of the yeast Hsp90 chaperone.[1]
Identifiers
Symbol HATPase_c
Pfam PF02518
InterPro IPR003594
SMART HATPase_c
SCOP 1ei1
SUPERFAMILY 1ei1
CDD cd00075

The GHKL domain (Gyrase, Hsp90, Histidine Kinase, MutL) is an evolutionary conserved protein domain.[2]

This family represents the structurally related ATPase domains of histidine kinase, DNA gyrase B and HSP90. This domain is found in several ATP-binding proteins for example: histidine kinase, DNA gyrase B, topoisomerases,[3] heat shock protein HSP90,[4][5][6] phytochrome-like ATPases and DNA mismatch repair proteins. More information about this protein can be found at Protein of the Month: DNA Topoisomerase.[7]

Subfamilies[edit]

  • Histidine kinase related protein, C-terminal IPR004358

Members[edit]

References[edit]

  1. ^ Prodromou C, Roe SM, Piper PW, Pearl LH (June 1997). "A molecular clamp in the crystal structure of the N-terminal domain of the yeast Hsp90 chaperone". Nat. Struct. Biol. 4 (6): 477–82. doi:10.1038/nsb0697-477. PMID 9187656. 
  2. ^ Dutta R, Inouye M (January 2000). "GHKL, an emergent ATPase/kinase superfamily". Trends Biochem. Sci. 25 (1): 24–8. doi:10.1016/S0968-0004(99)01503-0. PMID 10637609. 
  3. ^ Bellon S, Parsons JD, Wei Y, Hayakawa K, Swenson LL, Charifson PS, Lippke JA, Aldape R, Gross CH (May 2004). "Crystal Structures of Escherichia coli Topoisomerase IV ParE Subunit (24 and 43 Kilodaltons): a Single Residue Dictates Differences in Novobiocin Potency against Topoisomerase IV and DNA Gyrase". Antimicrob. Agents Chemother. 48 (5): 1856–64. doi:10.1128/AAC.48.5.1856-1864.2004. PMC 400558. PMID 15105144. 
  4. ^ Immormino RM, Dollins DE, Shaffer PL, Soldano KL, Walker MA, Gewirth DT (October 2004). "Ligand-induced conformational shift in the N-terminal domain of GRP94, an Hsp90 chaperone". J. Biol. Chem. 279 (44): 46162–71. doi:10.1074/jbc.M405253200. PMID 15292259. 
  5. ^ Roe SM, Ali MM, Meyer P, Vaughan CK, Panaretou B, Piper PW, Prodromou C, Pearl LH (January 2004). "The Mechanism of Hsp90 regulation by the protein kinase-specific cochaperone p50(cdc37)". Cell 116 (1): 87–98. doi:10.1016/S0092-8674(03)01027-4. PMID 14718169. 
  6. ^ Wright L, Barril X, Dymock B, Sheridan L, Surgenor A, Beswick M, Drysdale M, Collier A, Massey A, Davies N, Fink A, Fromont C, Aherne W, Boxall K, Sharp S, Workman P, Hubbard RE (June 2004). "Structure-activity relationships in purine-based inhibitor binding to HSP90 isoforms". Chem. Biol. 11 (6): 775–85. doi:10.1016/j.chembiol.2004.03.033. PMID 15217611. 
  7. ^ McDowall J (2006). "DNA Topoisomerase". Protein of the month. InterPro. 

This article incorporates text from the public domain Pfam and InterPro IPR003594

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This is the Wikipedia entry entitled "Hsp90". More...

Hsp90 Edit Wikipedia article

Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase
Hsp90.jpg
Solid ribbon model of the yeast Hsp90-dimer (α-helices = red, β-sheets = cyan, loops = grey) in complex with ATP (red stick diagram).[1]
Identifiers
Symbol HATPase_c
Pfam PF02518
Pfam clan CL0025
InterPro IPR003594
SMART SM00387
SCOP 1ei1
SUPERFAMILY 1ei1
Hsp90 protein
PDB 1ah6 EBI.jpg
Structure of the N-terminal domain of the yeast Hsp90 chaperone.[2]
Identifiers
Symbol Hsp90
Pfam PF00183
InterPro IPR020576
PROSITE PDOC00270
SCOP 1ah6
SUPERFAMILY 1ah6
Domain structure of the yeast heat-inducible Hsp90. Top: Crystallographic structure of the dimeric Hsp90.[1] Bound ATP molecules are represented by space filling spheres. Bottom: 1D sequence of the yeast Hsp90. NTD= N-terminal domain (red), MD = middle domain (green), CTD = C-terminal domain (blue).
Crystallographic structure of the ATP binding pocket of Hsp90 where ATP is represented by a ball and stick figure (carbon atoms = grey, nitrogen = blue, oxygen = red, phosphorus = orange) and Hsp90 is depicted as a solid surface (negatively charged = red, positively charged = blue, electrostatically neutral = grey).[1]
Pincer movement of Hsp90 coupled to the ATPase cycle. NTD = N-terminal domain, MD = middle domain, CTD = C-terminal domain.
The Hsp90 chaperone cycle. X/Y represents an immature incompletely folded protein such a steroid receptor. Hsp40, Hsp70, and p23 are partner chaperones while Hop is a co-chaperone. Also, X-X represents a mature properly folded protein dimer.

Hsp90 (heat shock protein 90) 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.

Heat shock proteins, as a class, are among the most highly expressed cellular proteins across all species.[3] As their name implies, heat shock proteins protect cells when stressed by elevated temperatures. They account for 1–2% of total protein in unstressed cells. However, when cells are heated, the fraction of heat shock proteins increases to 4–6% of cellular proteins.[4]

Heat shock protein 90 (Hsp90) is one of the most common of the heat-related proteins. The "90" comes from the fact that it weighs roughly 90 kiloDaltons. A 90 kDa protein is considered fairly large for a non-fibrous protein. Hsp90 is found in bacteria and all branches of eukarya, but it is apparently absent in archaea.[5] Whereas cytoplasmic Hsp90 is essential for viability under all conditions in eukaryotes, the bacterial homologue HtpG is dispensable under non-heat stress conditions.[6]

This protein was first isolated by extracting proteins from cells stressed by heating, dehydrating or by other means, all of which caused the cell’s proteins to begin to denature.[7] However it was later discovered that Hsp90 also has essential functions in unstressed cells.

Isoforms

Hsp90 is highly conserved and expressed in a variety of different organisms from bacteria to mammals – including the prokaryotic analogue HtpG (high-temperature protein G) with 40% sequence identity and 55% similarity to the human protein.[5] Yeast Hsp90 is 60% identical to human Hsp90α.

In mammalian cells, there are two or more genes encoding cytosolic Hsp90 homologues,[5] with the human Hsp90α showing 85% sequence identity to Hsp90β.[8] The α- and the β-forms are thought to be the result of a gene duplication event that occurred millions of years ago.[5]

The five functional human genes encoding Hsp90 protein isoforms are listed below:[8]

family subcellular
location
subfamily gene protein
HSP90A cytosolic HSP90AA
(inducible)
HSP90AA1 Hsp90-α1
HSP90AA2 Hsp90-α2
HSP90AB
(constitutively expressed)
HSP90AB1 Hsp90-β
HSP90B endoplasmic
reticulum
HSP90B1 Endoplasmin/
GRP-94
TRAP mitochondrial TRAP1 TNF Receptor-
Associated Protein 1

There are 12 human pseudogenes (non-functional genes) that encode additional Hsp90 isoforms that are not expressed as proteins.

A membrane-associated variant of cytosolic Hsp90, lacking an ATP-binding site, has recently been identified and was named Hsp90N.[9] This HSP90α-Δ-N transcript is a chimera, with the first 105 bp of the coding sequence derived from the CD47 gene on chromosome 3q13.2, and the remaining coding sequence derived from HSP90AA1.[8] However, gene-encoding Hsp90N was later proven to be non-existent in human genome. It is possibly a cloning artifact or a product of chromosomal rearrangement occurring in a single cell line.[10]

Structure

Common features

The overall structure of Hsp90 is similar to that of other proteins in that it contains all of the common secondary structural elements (i.e., alpha helixes, beta pleated sheets, and random coils). Being a cytoplasmic protein requires that the protein be globular in structure, that is largely non-polar on the inside and polar on the outside, so as to be dissolved by water. Hsp90 contains nine helices and eight anti-parallel beta pleated sheets, which combine to form several alpha/beta sandwiches. The 310 helices make up approximately 11% of the protein's amino acid residues, which is much higher than the average 4% in other proteins.[11]

Domain structure

Hsp90 consists of four structural domains:[12][13][14]

  • a highly conserved N-terminal domain (NTD) of ~25 kDa
  • a "charged linker" region, that connects the N-terminus with the middle domain
  • a middle domain (MD) of ~40 kDa
  • a C-terminal domain (CTD) of ~12 kDa.

Crystal structures are available for the N-terminal domain of yeast and human Hsp90,[15][16][17] for complexes of the N-terminus with inhibitors and nucleotides,[15][16] and for the middle domain of yeast Hsp90.[18] Recently structures for full length Hsp90 from E. coli (2IOP, 2IOQ),[19] yeast (2CG9, 2CGE),[20] and the dog endoplasmic reticulum (2O1U, 2O1V)[21] were elucidated.[22]

Hsp90 forms homodimers where the contact sites are localized within the C-terminus in the open conformation of the dimer. The N-termini also come in contact in the closed conformation of the dimer.[23]

N-terminal domain

The N-terminal domain shows homology not only among members of the Hsp90 chaperone family but also to members of the ATPase/kinase GHKL (Gyrase, Hsp90, Histidine Kinase, MutL) superfamily.[13]

A common binding pocket for ATP and the inhibitor geldanamycin is situated in the N-terminal domain.[15][16] Amino acids that are directly involved in the interaction with ATP are Leu34, Asn37, Asp79, Asn92, Lys98, Gly121, and Phe124. In addition, Mg2+ and several water molecules form bridging electrostatic and hydrogen bonding interactions, respectively, between Hsp90 and ATP. In addition, Glu33 is required for ATP hydrolysis.

Middle domain

The middle domain is divided into three regions:

  • a 3-layer α-β-α sandwich
  • a 3-turn α-helix and irregular loops
  • a 6-turn α-helix.[13]

The MD is also involved in client protein binding. For example, proteins known to interact this the Hsp90 MD include PKB/Akt1, eNOS,[24][25] Aha1, Hch1. Furthermore, substrate binding (e.g., by Aha1 and Hch1) to the MD is also known to increase the ATPase activity of Hsp90.[18][26]

C-terminal domain

The C-terminal domain possesses an alternative ATP-binding site, which becomes accessible when the N-terminal Bergerat pocket is occupied.[27][28]

At the very C-terminal end of the protein is the tetratricopeptide repeat (TPR) motif recognition site, the conserved MEEVD pentapeptide, that is responsible for the interaction with co-factors such as the immunophilins FKBP51 and FKBP52, the stress induced phosphoprotein 1 (Sti1/Hop), cyclophilin-40, PP5, Tom70, and many more.[29]

Mechanism

The Hsp90 protein contains three functional domains, the ATP-binding, protein-binding, and dimerizing domain, each of which playing a crucial role in the function of the protein.

ATP binding

The region of the protein near the N-terminus has a high-affinity ATP-binding site. The ATP binds to a sizable cleft in the side of protein, which is 15 Å (1.5 nanometres) deep. This cleft has a high affinity for ATP, and when given a suitable protein substrate, Hsp90 cleaves the ATP into ADP and Pi. Direct inhibitors of ATP binding or allosteric inhibitors of either ATP binding or ATPase activity can block Hsp90 function.[11] Another interesting feature of the ATP-binding region of Hsp90 is that it has a “lid” that is open during the ADP-bound state and closed in the ATP-bound state,[30] in the open conformation, the lid has no intraprotein interaction, and when closed comes into contact with several residues.[31] The contribution of this lid to the activity of Hsp90 has been probed with site-directed mutagenesis. The Ala107Asp mutant stabilizing the closed conformation of the protein through the formation of additional hydrogen bonds substantially increases ATPase activity while leaving the AMP+PnP conformation unchanged.[31]

The ATPase-binding region of Hsp90 is currently under intense study, because it is the principal binding site of drugs targeting this protein.[32] Antitumor drugs targeting this section of Hsp90 include the antibiotics geldanamycin,[11][33] herbimycin, radicicol, deguelin,[34] derrubone,[35] macbecin,[36] and beta-lactams.[37]

Protein binding

The protein-binding region of Hsp90 is located toward the C-terminus of the amino sequence. The Hsp90 protein can adopt two major conformational states. The first is an open ATP-bound state and the second is a closed ADP-bound state. Thus, ATP hydrolysis drives what is commonly referred to as a “pincer-type” conformational change in the protein binding site.[38]

Hsp90, while in the open conformation, leaves some hydrophobic residues exposed, to which unfolded and misfolded proteins that have unusual hydrophobic regions exposed are recruited with high affinity.[39] When a bound substrate is in place, the energy-releasing ATP hydrolysis by the ATPase function near the N-terminal domain forces conformational changes that clamp the Hsp90 down onto the substrate.[31] In a reaction similar to that of other molecular clamp proteins like GyrB and MutL, this site drives virtually all of the protein folding functions that Hsp90 plays a role in. In contrast, MutL and GyrB function as topoisomerases and use a charge clamp with a high amount of positively charged sidechains that is electrostatically attracted to the negative backbone of DNA.[40]

The ability of Hsp90 to clamp onto proteins allows it perform several functions including assisting folding, preventing aggregation, and facilitating transport.

Function

Normal cells

In unstressed cells, Hsp90 plays a number of important roles, which include assisting folding, intracellular transport, maintenance, and degradation of proteins as well as facilitating cell signaling.

Protein folding and role as chaperone

Hsp90 is known to associate with the non-native structures of many proteins, which has led to the proposal that Hsp90 is involved in protein folding in general.[41] Furthermore Hsp90 has been shown to suppress the aggregation of a wide range of "client" or "substrate" proteins and hence acts as a general protective chaperone.[42][43][44] However Hsp90 is somewhat more selective than other chaperones.[45]

Protein degradation

Eukaryotic proteins that are no longer needed or are misfolded or otherwise damaged are usually marked for destruction by the polyubiquitation pathway. These ubiquitinated proteins are recognized and degraded by the 26S proteasome.[46][47] Hence the 26S proteasome is an integral part of the cell's mechanism to degrade proteins. Furthermore a constant supply of functional Hsp90 is needed to maintain the tertiary structure of the proteasome.[48] Finally experiments done with heat sensitive Hsp90 mutants and the 26S proteasome suggest that Hsp90 is responsible for most, if not all, of the ATPase activity of the proteasome.[46]

Interaction with steroid receptors

Schematic diagram of the translocation of the glucocorticoid receptor (GR) from the cytoplasm into the nucleus assisted by Hsp90 (90).[49] In the cytoplasm, GR is complexed with Hsp90 and the immunophilin FKBP51 (51). Binding of hormone to GR causes a conformational change in the complex, which results in exchange of FKBP51 for FKBP52 (52). FKBP52 in turn binds the dynein (dyn) motor protein that attaches to the cytoskeleton and transports the GR complex into the nucleus. Once in the nucleus, the complex disassembles releasing GR, which dimerizes and binds to DNA where it facilitates transcription of DNA into mRNA.

The glucocorticoid receptor (GR) is the most thoroughly studied example of a steroid receptor whose function is crucially dependent on interactions with Hsp90.[50][51] In the absence of the steroid hormone cortisol, GR resides in the cytosol complexed with several chaperone proteins including Hsp90 (see figure to the right). These chaperones maintain the GR in a state capable of binding hormone. A second role of Hsp90 is to bind immunophilins (e.g., FKBP52) that attach the GR complex to the dynein protein trafficking pathway, which translocates the activated receptor from the cytoplasm into the nucleus.[52] Once in the nucleus, the GR dimerizes and binds to specific sequences of DNA and thereby upregulates the expression of GR responsive genes. Hsp90 is also required for the proper functioning of several other steroid receptors, including those responsible for the binding of aldosterone,[53] androgen,[54] estrogen,[55] and progesterone.[56]

Cancerous cells

Cancerous cells overexpress a number of proteins, including growth factor receptors, such as EGFR,[57] or signal transduction proteins such as PI3K and AKT (Inhibition of these proteins may trigger apoptosis). Hsp90 stabilizes various growth factor receptors[58] and some signaling molecules including PI3K and AKT proteins. Hence inhibition of Hsp90 may induce apoptosis through inhibition of the PI3K/AKT signaling pathway and growth factor signaling generally.[15][59]

Another important role of Hsp90 in cancer is the stabilization of mutant proteins such as v-Src, the fusion oncogene Bcr/Abl, and mutant forms of p53 that appear during cell transformation. It appears that Hsp90 can act as a "protector" of less stable proteins produced by DNA mutations.[60]

Hsp90 is also required for induction of vascular endothelial growth factor (VEGF) and nitric oxide synthase (NOS).[25] Both are important for de novo angiogenesis that is required for tumour growth beyond the limit of diffusion distance of oxygen in tissues.[60] It also promotes the invasion step of metastasis by assisting the matrix metalloproteinase MMP2.[61] Together with its co-chaperones, Hsp90 modulates tumour cell apoptosis "mediated through effects on AKT,[24] tumor necrosis factor receptors (TNFR) and nuclear factor-κB (NF-κB) function."[62] Also, Hsp90 participates in many key processes in oncogenesis such as self-sufficiency in growth signals, stabilization of mutant proteins, angiogenesis, and metastasis.

Clinical significance

Hsp90 plays apparently conflicting roles in the cell, as it is essential for both the creation and the maintenance as well as the destruction of proteins. Its normal function is critical to maintaining the health of cells, whereas its dysregulation may contribute to carcinogenesis. The ability of this chaperone to both stabilize the 26S proteasome (which enables the cell to degrade unwanted and/or harmful proteins) and to stabilize kinases against the same proteasome demonstrates its functional diversity. The uses of Hsp90 inhibitors in cancer treatment highlight Hsp90's importance as a therapeutic target.[63]

Targeting Hsp90 with drugs has shown promising effects in clinical trials. For example, the Hsp90 inhibitor geldanamycin has been used as an anti-tumor agent.[11] The drug was originally thought to function as a kinase inhibitor but was subsequently shown to be an Hsp90 inhibitor where it uses a compact conformation to insert itself into the ATP binding site.[11]

HSP90 beta has been identified as one of the autoantigenic biomarkers and targets involved in human ovarian autoimmune disease leading to ovarian failure and thereby infertility.[64]

Prediction and validation of the immunodominant epitope/s of HSP90 beta protein has been demonstrated using sera from infertile women having anti-HSP90 autoantibodies. The decapeptide EP6 (380-389)is a major immunogenic epitope of HSP90 followed by EP1 (1-12) and EP8 (488-498). Knowledge of binding epitopes on the autoantigen is necessary to understand the subsequent pathologic events. Predicted 3D structures of these peptides demonstrated that they exist in the loop conformation, which is the most mobile part of the protein. Also, analysis of the sequences of HSP90 beta across several species reveals that EP6 peptide forms a part of a well-conserved motif. A polyclonal antibody generated to the immunodominant epitope- EP6 confirms similar biochemical and cellular immunoreactivity as seen with the patients' sera with anti-HSP90 autoantibodies. The study might generate new tools for the detection of disease-inducing epitopes and a possible therapeutic intervention.[65]

Evolution

Sequence alignments of Hsp90 have shown the protein to have about 40% sequence identity across all homologs, indicating that it is a highly conserved protein. There are two homologs, found in the cytosol and endoplasmic reticulum respectively. The presence of these two homologs was likely caused by a gene duplication event very early in the evolution of eukaryotes that may have accompanied the evolution of the endoplasmic reticulum or the nucleus. This inference is supported by the fact that the duplication is found in Giardia lamblia, one of the earliest branching eukaryotic species. At least 2 other subsequent gene duplications occurred, which explains the different forms of Hsp90 found in fungi and vertebrates. One divergence produced cognate and heat-induced forms of Hsp90 in Saccharomyces cerevisiae, while the second gene duplication event in the cytosolic branch produced the alpha and beta subfamilies of sequences that are found in all vertebrates. In a phylogenetic tree based on Hsp90 sequences, it was found that plants and animals are more closely related to each other than to fungi.[66] Similar to the Hsp90 protein, the gene for Hsp70 protein also underwent duplication at a very early stage in the formation of eukaryotic cells and the homologs in the cytosol and endoplasmic reticulum resulted from this gene duplication event.[67] These gene duplication events are important in terms of the origin of the eukaryotic cell and of the endoplasmic reticulum.[68][69]

See also

References

  1. ^ a b c PDB 2CG9; Ali MM, Roe SM, Vaughan CK, Meyer P, Panaretou B, Piper PW, Prodromou C, Pearl LH (April 2006). "Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex". Nature 440 (7087): 1013–7. doi:10.1038/nature04716. PMID 16625188. 
  2. ^ Prodromou C, Roe SM, Piper PW, Pearl LH (June 1997). "A molecular clamp in the crystal structure of the N-terminal domain of the yeast Hsp90 chaperone". Nat. Struct. Biol. 4 (6): 477–82. doi:10.1038/nsb0697-477. PMID 9187656. 
  3. ^ Csermely P, Schnaider T, Soti C, Prohászka Z, Nardai G (August 1998). "The 90-kDa molecular chaperone family: structure, function, and clinical applications. A comprehensive review". Pharmacol. Ther. 79 (2): 129–68. doi:10.1016/S0163-7258(98)00013-8. PMID 9749880. 
  4. ^ Crevel G, Bates H, Huikeshoven H, Cotterill S (1 June 2001). "The Drosophila Dpit47 protein is a nuclear Hsp90 co-chaperone that interacts with DNA polymerase alpha". J. Cell. Sci. 114 (Pt 11): 2015–25. PMID 11493638. 
  5. ^ a b c d Chen B, Zhong D, Monteiro A (2006). "Comparative genomics and evolution of the HSP90 family of genes across all kingdoms of organisms". BMC Genomics 7: 156. doi:10.1186/1471-2164-7-156. PMC 1525184. PMID 16780600. 
  6. ^ Thomas JG, Baneyx F (October 1998). "Roles of the Escherichia coli Small Heat Shock Proteins IbpA and IbpB in Thermal Stress Management: Comparison with ClpA, ClpB, and HtpG In Vivo". J. Bacteriol. 180 (19): 5165–72. PMC 107554. PMID 9748451. 
  7. ^ Prodromou C, Panaretou B, Chohan S, Siligardi G, O'Brien R, Ladbury JE, Roe SM, Piper PW, Pearl LH (August 2000). "The ATPase cycle of Hsp90 drives a molecular 'clamp' via transient dimerization of the N-terminal domains". EMBO J. 19 (16): 4383–92. doi:10.1093/emboj/19.16.4383. PMC 302038. PMID 10944121. 
  8. ^ a b c Chen B, Piel WH, Gui L, Bruford E, Monteiro A (December 2005). "The Hsp90 family of genes in the human genome: insights into their divergence and evolution". Genomics 86 (6): 627–37. doi:10.1016/j.ygeno.2005.08.012. PMID 16269234. 
  9. ^ Grammatikakis N, Vultur A, Ramana CV, Siganou A, Schweinfest CW, Watson DK, Raptis L (March 2002). "The role of Hsp90N, a new member of the Hsp90 family, in signal transduction and neoplastic transformation". J. Biol. Chem. 277 (10): 8312–20. doi:10.1074/jbc.M109200200. PMID 11751906. 
  10. ^ Zurawska A, Urbanski J, Bieganowski P (November 2008). "Hsp90n - An accidental product of a fortuitous chromosomal translocation rather than a regular Hsp90 family member of human proteome". Biochimica et Biophysica Acta 1784 (11): 1844–6. doi:10.1016/j.bbapap.2008.06.013. PMID 18638579. 
  11. ^ a b c d e Goetz MP, Toft DO, Ames MM, Erlichman C (August 2003). "The Hsp90 chaperone complex as a novel target for cancer therapy". Ann. Oncol. 14 (8): 1169–76. doi:10.1093/annonc/mdg316. PMID 12881371. 
  12. ^ Pearl LH, Prodromou C (February 2000). "Structure and in vivo function of Hsp90". Curr. Opin. Struct. Biol. 10 (1): 46–51. doi:10.1016/S0959-440X(99)00047-0. PMID 10679459. 
  13. ^ a b c Prodromou C, Pearl LH (October 2003). "Structure and functional relationships of Hsp90". Curr Cancer Drug Targets 3 (5): 301–23. doi:10.2174/1568009033481877. PMID 14529383. 
  14. ^ Pearl LH, Prodromou C (2001). "Structure, function, and mechanism of the Hsp90 molecular chaperone". Adv. Protein Chem. Advances in Protein Chemistry 59: 157–86. doi:10.1016/S0065-3233(01)59005-1. ISBN 978-0-12-034259-4. PMID 11868271. 
  15. ^ a b c d Stebbins CE, Russo AA, Schneider C, Rosen N, Hartl FU, Pavletich NP (April 1997). "Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent". Cell 89 (2): 239–50. doi:10.1016/S0092-8674(00)80203-2. PMID 9108479. 
  16. ^ a b c Prodromou C, Roe SM, O'Brien R, Ladbury JE, Piper PW, Pearl LH (July 1997). "Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone". Cell 90 (1): 65–75. doi:10.1016/S0092-8674(00)80314-1. PMID 9230303. 
  17. ^ Prodromou C, Roe SM, Piper PW, Pearl LH (June 1997). "A molecular clamp in the crystal structure of the N-terminal domain of the yeast Hsp90 chaperone". Nat. Struct. Biol. 4 (6): 477–82. doi:10.1038/nsb0697-477. PMID 9187656. 
  18. ^ a b Meyer P, Prodromou C, Hu B, Vaughan C, Roe SM, Panaretou B, Piper PW, Pearl LH (March 2003). "Structural and functional analysis of the middle segment of hsp90: implications for ATP hydrolysis and client protein and cochaperone interactions". Mol. Cell 11 (3): 647–58. doi:10.1016/S1097-2765(03)00065-0. PMID 12667448. 
  19. ^ Shiau AK, Harris SF, Southworth DR, Agard DA (October 2006). "Structural Analysis of E. coli hsp90 reveals dramatic nucleotide-dependent conformational rearrangements". Cell 127 (2): 329–40. doi:10.1016/j.cell.2006.09.027. PMID 17055434. 
  20. ^ Ali MM, Roe SM, Vaughan CK, Meyer P, Panaretou B, Piper PW, Prodromou C, Pearl LH' (April 2006). "Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex". Nature 440 (7087): 1013–7. doi:10.1038/nature04716. PMID 16625188. 
  21. ^ Dollins DE, Warren JJ, Immormino RM, Gewirth DT (October 2007). "Structures of GRP94-nucleotide complexes reveal mechanistic differences between the hsp90 chaperones". Mol. Cell 28 (1): 41–56. doi:10.1016/j.molcel.2007.08.024. PMC 2094010. PMID 17936703. 
  22. ^ Wandinger SK, Richter K, Buchner J (July 2008). "The hsp90 chaperone machinery". J. Biol. Chem. 283 (27): 18473–7. doi:10.1074/jbc.R800007200. PMID 18442971. 
  23. ^ Meyer P, Prodromou C, Hu B, Vaughan C, Roe SM, Panaretou B, Piper PW, Pearl LH. (March 2003). "Structural and functional analysis of the middle segment of hsp90: implications for ATP hydrolysis and client protein and cochaperone interactions". Mol. Cell 11 (3): 647–58. doi:10.1016/S1097-2765(03)00065-0. PMID 12667448. 
  24. ^ a b Sato S, Fujita N, Tsuruo T (September 2000). "Modulation of Akt kinase activity by binding to Hsp90". Proc. Natl. Acad. Sci. U.S.A. 97 (20): 10832–7. doi:10.1073/pnas.170276797. PMC 27109. PMID 10995457. 
  25. ^ a b Fontana J, Fulton D, Chen Y, Fairchild TA, McCabe TJ, Fujita N, Tsuruo T, Sessa WC (May 2002). "Domain mapping studies reveal that the M domain of hsp90 serves as a molecular scaffold to regulate Akt-dependent phosphorylation of endothelial nitric oxide synthase and NO release". Circ. Res. 90 (8): 866–73. doi:10.1161/01.RES.0000016837.26733.BE. PMID 11988487. 
  26. ^ Panaretou B, Siligardi G, Meyer P, Maloney A, Sullivan JK, Singh S, Millson SH, Clarke PA, Naaby-Hansen S, Stein R, Cramer R, Mollapour M, Workman P, Piper PW, Pearl LH, Prodromou C (December 2002). "Activation of the ATPase activity of hsp90 by the stress-regulated cochaperone aha1". Mol. Cell 10 (6): 1307–18. doi:10.1016/S1097-2765(02)00785-2. PMID 12504007. 
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  39. ^ Xu Z, Horwich AL, Sigler PB (August 1997). "The crystal structure of the asymmetric GroEL-GroES-(ADP)7 chaperonin complex". Nature 388 (6644): 741–50. doi:10.1038/41944. PMID 9285585. 
  40. ^ Kampranis SC, Bates AD, Maxwell A (July 1999). "A model for the mechanism of strand passage by DNA gyrase". Proc. Natl. Acad. Sci. U.S.A. 96 (15): 8414–9. doi:10.1073/pnas.96.15.8414. PMC 17530. PMID 10411889. 
  41. ^ Buchner J (April 1999). "Hsp90 & Co. - a holding for folding". Trends Biochem. Sci. 24 (4): 136–41. doi:10.1016/S0968-0004(99)01373-0. PMID 10322418. 
  42. ^ Miyata Y, Yahara I (April 1992). "The 90-kDa heat shock protein, Hsp90, binds and protects casein kinase II from self-aggregation and enhances its kinase activity". J. Biol. Chem. 267 (10): 7042–7. PMID 1551911. 
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  44. ^ Jakob U, Lilie H, Meyer I, Buchner J (March 1995). "Transient interaction of Hsp90 with early unfolding intermediates of citrate synthase. Implications for heat shock in vivo". J. Biol. Chem. 270 (13): 7288–94. doi:10.1074/jbc.270.13.7288. PMID 7706269. 
  45. ^ Picard D (October 2002). "Heat-shock protein 90, a chaperone for folding and regulation". Cell. Mol. Life Sci. 59 (10): 1640–8. doi:10.1007/PL00012491. PMID 12475174. 
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External links

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase Provide feedback

This family represents the structurally related ATPase domains of histidine kinase, DNA gyrase B and HSP90.

Literature references

  1. Li Y, Bahti P, Shaw N, Song G, Chen S, Zhang X, Zhang M, Cheng C, Yin J, Zhu JY, Zhang H, Che D, Xu H, Abbas A, Wang BC, Liu ZJ;, Proteins 2008;71:2109-13.: Crystal structure of a novel non-Pfam protein AF1514 from Archeoglobus fulgidus DSM 4304 solved by S-SAD using a Cr X-ray source. PUBMED:18361456 EPMC:18361456


Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR003594

This domain is found in several ATP-binding proteins for example: histidine kinase, DNA gyrase B, topoisomerases [PUBMED:15105144], heat shock protein HSP90 [PUBMED:15292259, PUBMED:14718169, PUBMED:15217611], phytochrome-like ATPases and DNA mismatch repair proteins. The fold of this domain consists of two layers, alpha/beta, which contains an 8-stranded mixed beta-sheet.

More information about this protein can be found at Protein of the Month: DNA Topoisomerase [PUBMED:].

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan His_Kinase_A (CL0025), which has the following description:

This is the dimerisation and phospho-acceptor domain of a sub-family of histidine kinases. It shares sequence similarity with Pfam:PF00512 and Pfam:PF07536. It is usually found adjacent to a C-terminal ATPase domain (Pfam:PF02518). This domain is found in a wide range of Bacteria and also several Archaea. It comprises one of the fundamental units of the two-component signal transduction system [2-7].

The clan contains the following 9 members:

DUF2328 HATPase_c HATPase_c_2 HATPase_c_3 HATPase_c_5 HisKA HisKA_2 HisKA_3 HWE_HK

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

View options

We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

  Seed
(659)
Full
(129386)
Representative proteomes NCBI
(119054)
Meta
(19749)
RP15
(12473)
RP35
(24121)
RP55
(30935)
RP75
(36085)
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PP/heatmap 1              
Pfam viewer View  View             

1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

  Seed
(659)
Full
(129386)
Representative proteomes NCBI
(119054)
Meta
(19749)
RP15
(12473)
RP35
(24121)
RP55
(30935)
RP75
(36085)
Alignment:
Format:
Order:
Sequence:
Gaps:
Download/view:

Download options

We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

  Seed
(659)
Full
(129386)
Representative proteomes NCBI
(119054)
Meta
(19749)
RP15
(12473)
RP35
(24121)
RP55
(30935)
RP75
(36085)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: SMART
Previous IDs: none
Type: Domain
Author: SMART, Griffiths-Jones SR
Number in seed: 659
Number in full: 129386
Average length of the domain: 113.50 aa
Average identity of full alignment: 24 %
Average coverage of the sequence by the domain: 18.95 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 21.3 21.3
Trusted cut-off 21.3 21.3
Noise cut-off 21.2 21.2
Model length: 111
Family (HMM) version: 21
Download: download the raw HMM for this family

Species distribution

Sunburst controls

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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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Tree controls

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The tree shows the occurrence of this domain across different species. More...

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Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.

Interactions

There are 11 interactions for this family. More...

CDC37_M FbpA DNA_gyraseB HSP90 HATPase_c HisKA CheW Topo-VIb_trans DNA_mis_repair H-kinase_dim BCDHK_Adom3

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the HATPase_c domain has been found. There are 397 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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