Summary: Hsp90 protein
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Hsp90 Edit Wikipedia article
|Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase|
Structure of the N-terminal domain of the yeast Hsp90 chaperone.
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. 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.
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. Whereas cytoplasmic Hsp90 is essential for viability under all conditions in eukaryotes, the bacterial homologue HtpG is dispensable under non-heat stress conditions.
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. However it was later discovered that Hsp90 also has essential functions in unstressed cells.
- 1 Isoforms
- 2 Structure
- 3 Mechanism
- 4 Function
- 5 Clinical significance
- 6 Evolution
- 7 See also
- 8 References
- 9 External links
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. Yeast Hsp90 is 60% identical to human Hsp90α.
In mammalian cells, there are two or more genes encoding cytosolic Hsp90 homologues, with the human Hsp90α showing 85% sequence identity to Hsp90β. The α- and the β-forms are thought to be the result of a gene duplication event that occurred millions of years ago.
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. 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. 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.
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.
- 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, for complexes of the N-terminus with inhibitors and nucleotides, and for the middle domain of yeast Hsp90. Recently structures for full length Hsp90 from E. coli ( , ), yeast ( , ), and the dog endoplasmic reticulum ( , ) were elucidated.
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.
A common binding pocket for ATP and the inhibitor geldanamycin is situated in the N-terminal domain. 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.
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.
The MD is also involved in client protein binding. For example, proteins known to interact this the Hsp90 MD include PKB/Akt1, eNOS, Aha1, Hch1. Furthermore, substrate binding (e.g., by Aha1 and Hch1) to the MD is also known to increase the ATPase activity of Hsp90.
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.
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.
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. 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, in the open conformation, the lid has no intraprotein interaction, and when closed comes into contact with several residues. 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.
The ATPase-binding region of Hsp90 is currently under intense study, because it is the principal binding site of drugs targeting this protein. Antitumor drugs targeting this section of Hsp90 include the antibiotics geldanamycin, herbimycin, radicicol, deguelin, derrubone, macbecin, and beta-lactams.
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.
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. 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. 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.
The ability of Hsp90 to clamp onto proteins allows it perform several functions including assisting folding, preventing aggregation, and facilitating transport.
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. 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. However Hsp90 is somewhat more selective than other chaperones.
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. 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. 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.
Interaction with steroid receptors
The glucocorticoid receptor (GR) is the most thoroughly studied example of a steroid receptor whose function is crucially dependent on interactions with Hsp90. 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. 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, androgen, estrogen, and progesterone.
Cancerous cells overexpress a number of proteins, including growth factor receptors, such as EGFR, or signal transduction proteins such as PI3K and AKT (Inhibition of these proteins may trigger apoptosis). Hsp90 stabilizes various growth factor receptors 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.
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.
Hsp90 is also required for induction of vascular endothelial growth factor (VEGF) and nitric oxide synthase (NOS). Both are important for de novo angiogenesis that is required for tumour growth beyond the limit of diffusion distance of oxygen in tissues. It also promotes the invasion step of metastasis by assisting the matrix metalloproteinase MMP2. Together with its co-chaperones, Hsp90 modulates tumour cell apoptosis "mediated through effects on AKT, tumor necrosis factor receptors (TNFR) and nuclear factor-κB (NF-κB) function." Also, Hsp90 participates in many key processes in oncogenesis such as self-sufficiency in growth signals, stabilization of mutant proteins, angiogenesis, and metastasis.
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.
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. 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.
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.
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.
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. 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. These gene duplication events are important in terms of the origin of the eukaryotic cell and of the endoplasmic reticulum.
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- Pratt WB, Morishima Y, Murphy M, Harrell M (2006). "Chaperoning of glucocorticoid receptors". Handb Exp Pharmacol. Handbook of Experimental Pharmacology 172 (172): 111–38. doi:10.1007/3-540-29717-0_5. ISBN 3-540-25875-2. PMID 16610357.
- Grad I, Picard D (September 2007). "The glucocorticoid responses are shaped by molecular chaperones". Mol. Cell. Endocrinol. 275 (1–2): 2–12. doi:10.1016/j.mce.2007.05.018. PMID 17628337.
- Pratt WB, Galigniana MD, Morishima Y, Murphy PJ (2004). "Role of molecular chaperones in steroid receptor action". Essays Biochem. 40: 41–58. PMID 15242338.
- Rafestin-Oblin ME, Couette B, Radanyi C, Lombes M, Baulieu EE (June 1989). "Mineralocorticosteroid receptor of the chick intestine. Oligomeric structure and transformation". J. Biol. Chem. 264 (16): 9304–9. PMID 2542305.
- Joab I, Radanyi C, Renoir M, Buchou T, Catelli MG, Binart N, Mester J, Baulieu EE (1984). "Common non-hormone binding component in non-transformed chick oviduct receptors of four steroid hormones". Nature 308 (5962): 850–3. doi:10.1038/308850a0. PMID 6201744.
- Redeuilh G, Moncharmont B, Secco C, Baulieu EE (May 1987). "Subunit composition of the molybdate-stabilized "8-9 S" nontransformed estradiol receptor purified from calf uterus". J. Biol. Chem. 262 (15): 6969–75. PMID 3584104.
- Catelli MG, Binart N, Jung-Testas I, Renoir JM, Baulieu EE, Feramisco JR, Welch WJ (December 1985). "The common 90-kd protein component of non-transformed '8S' steroid receptors is a heat-shock protein". EMBO J. 4 (12): 3131–5. PMC 554632. PMID 2419124.
- Lurje G, Lenz HJ (2009). "EGFR Signaling and Drug Discovery". Oncology 77 (6): 400–410. doi:10.1159/000279388. PMID 20130423.
- Sawai A, Chandarlapaty S, Greulich H, Gonen M, Ye Q, Arteaga CL, Sellers W, Rosen N, Solit DB (January 2008). "Inhibition of Hsp90 down-regulates mutant epidermal growth factor receptor (EGFR) expression and sensitizes EGFR mutant tumors to paclitaxel". Cancer Res. 68 (2): 589–96. doi:10.1158/0008-5472.CAN-07-1570. PMID 18199556.
- Mohsin SK, Weiss HL, Gutierrez MC, Chamness GC, Schiff R, Digiovanna MP, Wang CX, Hilsenbeck SG, Osborne CK, Allred DC, Elledge R, Chang JC (April 2005). "Neoadjuvant trastuzumab induces apoptosis in primary breast cancers". J. Clin. Oncol. 23 (11): 2460–8. doi:10.1200/JCO.2005.00.661. PMID 15710948.
- Calderwood SK, Khaleque MA, Sawyer DB, Ciocca DR (March 2006). "Heat shock proteins in cancer: chaperones of tumorigenesis". Trends Biochem. Sci. 31 (3): 164–72. doi:10.1016/j.tibs.2006.01.006. PMID 16483782.
- Eustace BK, Sakurai T, Stewart JK, Yimlamai D, Unger C, Zehetmeier C, Lain B, Torella C, Henning SW, Beste G, Scroggins BT, Neckers L, Ilag LL, Jay DG (June 2004). "Functional proteomic screens reveal an essential extracellular role for hsp90 alpha in cancer cell invasiveness". Nat. Cell Biol. 6 (6): 507–14. doi:10.1038/ncb1131. PMID 15146192.
- Whitesell L, Lindquist SL (October 2005). "Hsp90 and the chaperoning of cancer". Nat. Rev. Cancer 5 (10): 761–72. doi:10.1038/nrc1716. PMID 16175177.
- Kim YS, Alarcon SV, Lee S, Lee MJ, Giaccone G, Neckers L, Trepel JB (2009). "Update on Hsp90 inhibitors in clinical trial". Curr Top Med Chem 9 (15): 1479–92. doi:10.2174/156802609789895728. PMID 19860730.
- Pires ES, Khole VV (2009). "A block in the road to fertility: autoantibodies to heat-shock protein 90-beta in human ovarian autoimmunity". Fertil Steril 92 (4): 1395–1409. doi:10.1016/j.fertnstert.2008.08.068. PMID 19022436.
- Pires ES, Choudhury AK, Idicula-Thomas S, Khole VV (2011). "Anti-HSP90 autoantibodies in sera of infertile women identify a dominant, conserved epitope EP6 (380-389) of HSP90 beta protein". Reprod Biol Endocrinol 9 (16): 13. doi:10.1186/1477-7827-9-1. PMC 3039567. PMID 21272367.
- Gupta RS (November 1995). "Phylogenetic analysis of the 90 kD heat shock family of protein sequences and an examination of the relationship among animals, plants, and fungi species". Mol. Biol. Evol. 12 (6): 1063–73. PMID 8524040.
- Gupta RS, Aitken K, Falah M, Singh B (April 1994). "Cloning of Giardia lamblia heat shock protein HSP70 homologs: implications regarding origin of eukaryotic cells and of endoplasmic reticulum". Proc. Natl. Acad. Sci. U.S.A. 91 (8): 2895–9. doi:10.1073/pnas.91.8.2895. PMC 43480. PMID 8159675.
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|Wikimedia Commons has media related to HSP90 heat-shock proteins.|
- Hsp90 Heat-Shock Proteins at the US National Library of Medicine Medical Subject Headings (MeSH)
- Didier Picard. "Hsp90 web site". VisibilityWeb. Retrieved 2008-07-07. "A web site for the community of scientists interested in the Hsp90 molecular chaperone machine."
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.
Hsp90 protein Provide feedback
No Pfam abstract.
Prodromou C, Roe SM, Piper PW, Pearl LH; , Nat Struct Biol 1997;4:477-482.: A molecular clamp in the crystal structure of the N-terminal domain of the yeast Hsp90 chaperone. PUBMED:9187656 EPMC:9187656
Internal database links
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR001404
Molecular chaperones, or heat shock proteins (Hsps) are ubiquitous proteins that act to maintain proper protein folding within the cell [PUBMED:11407116]. They assist in the folding of nascent polypeptide chains, and are also involved in the re-folding of denatured proteins following proteotoxic stress. As their name implies, the heat shock proteins were first identified as proteins that were up-regulated under conditions of elevated temperature. However, subsequent studies have shown that increased Hsp expression is induced by a variety of cellular stresses, including oxidative stress and inflammation. Five major Hsp families have been determined, and are categorized according to their molecular size (Hsp100, Hsp90, Hsp70, Hsp60, and the small Hsps). Hsps are involved in a variety of cellular processes that are ATP-dependent. These include: prevention of protein aggregation, protein degradation, protein trafficking, and maintenance of signalling proteins in a conformation that permits activation.
Hsp90 chaperones are unique in their ability to regulate a specific subset of cellular signalling proteins that have been implicated in disease processes, including intracellular protein kinases, steroid hormone receptors, and growth factor receptors [PUBMED:9521088].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||ATP binding (GO:0005524)|
|unfolded protein binding (GO:0051082)|
|Biological process||protein folding (GO:0006457)|
|response to stress (GO:0006950)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
Loading domain graphics...
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...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
- Pfam viewer
- an HTML-based viewer that uses DAS to retrieve alignment fragments on request
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
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.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
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.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
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 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...
If you find these logos useful in your own work, please consider citing the following article:
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.
|Number in seed:||11|
|Number in full:||5703|
|Average length of the domain:||358.50 aa|
|Average identity of full alignment:||32 %|
|Average coverage of the sequence by the domain:||66.61 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||13|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
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.
There are 2 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
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 HSP90 domain has been found. There are 350 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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