Hsp27

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Heat shock 27kDa protein 1
3q9p.png
HspB1 fragment. PDB 3q9p[1]
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols HSPB1 ; CMT2F; HMN2B; HS.76067; HSP27; HSP28; Hsp25; SRP27
External IDs OMIM602195 MGI96240 HomoloGene1180 ChEMBL: 5976 GeneCards: HSPB1 Gene
Orthologs
Species Human Mouse
Entrez 3315 15507
Ensembl ENSG00000106211 ENSMUSG00000004951
UniProt P04792 P14602
RefSeq (mRNA) NM_001540 NM_013560
RefSeq (protein) NP_001531 NP_038588
Location (UCSC) Chr 7:
75.93 – 75.93 Mb
Chr 5:
135.89 – 135.89 Mb
PubMed search [1] [2]

Heat shock protein 27 (Hsp27) also known as heat shock protein beta-1 (HSPB1) is a protein that in humans is encoded by the HSPB1 gene.[2][3]

Hsp27 is a chaperone of the sHsp (small heat shock protein) group among ubiquitin, α-crystallin, Hsp20 and others. The common functions of sHsps are chaperone activity, thermotolerance, inhibition of apoptosis, regulation of cell development, and cell differentiation. They also take part in signal transduction.

Structure[edit]

sHsps have some structural features in common: Very characteristic is a homologous and highly conserved amino acid sequence, the so-called α-crystallin-domain at the C-terminus. These sequences consist of 80 to 100 residues with a homology between 20% and 60% and form β-sheets, which are important for the formation of stable dimers.[4][5]

The N-terminus consists of a less conserved region, the so-called WD/EPF domain, followed by a short variable sequence with a rather conservative site near the C-terminus of this domain. The C-terminal part of the sHsps consists of the above mentioned α-crystallin domain, followed by a variable sequence with high motility and flexibility.[6]

This C-terminal tail appears in many mammalian sHsps (e.g. mouse Hsp25, αA-crystallin) and has no homology. It is highly flexible and polar because of its negative charges.[7] Probably it functions as a mediator of solubility for hydrophobic sHsps and it stabilizes the protein and protein/substrate complexes. This was shown by elimination of the C-terminal tail in Hsp27Δ182-205[8] and in Hsp25Δ18.[9]

Oligomerization[edit]

The N-terminus with its WD/EPF-region is essential for the development of high molecular oligomers,[10][11] which exclusively have chaperone activity in vitro. Hsp27-oligomers probably consist of stable dimers, which are formed by two α-crystallin-domains of neighbouring monomers,[6] which was shown with the proteins MjHSP16.5 from Methanocaldococcus jannaschii[4] and wheat Hsp16.9.[5] The stable dimers aggregate to tetramers and finally form unstable oligomers.

The oligomerization of Hsp27 is a dynamic process: There is a balance between stable dimers respectively tetramers and instable oligomers (up to 800 kDa) consisting of 16 to 32 subunits and a high exchange rate of subunits.[11][12][13] The oligomerization depends on the physiology of the cells, the phosphorylation status of Hsp27 and the exposure to stress. Stress induces an increase of expression (after hours) and phosphorylation (after several minutes) of Hsp27. Stimulation of the p38 MAP kinase cascade by differentiating agents, mitogens, inflammatory cytokines such as TNFα and IL-1β, hydrogen peroxide and other oxidants,[14] leads to the activation of MAPKAP kinases 2 and 3 which directly phosphorylate mammalian sHsps.[13] The phosphorylation plays an important role for the formation of oligomers in exponentially growing cells in vitro, but the oligomerization in tumor cells growing in vivo or growing at confluence in vitro is dependent on cell-cell contact, but not on the phosphorylation status.[15] Furthermore, it was shown that HSP27 contains an Argpyrimidine modification. [16]

In all probability, the oligomerization status is connected with the chaperone activity: aggregates of large oligomers have high chaperone activity, whereas dimers have no chaperone activity.[6] Therefore it is clear, that a formation of large aggregates takes place under heat shock.[12]

Cellular Localization[edit]

Hsp27 appears in many cell types, especially all types of muscle cells. It is located mainly in the cytosol, but also in the perinuclear region, endoplasmatic reticulum, and nucleus. It is overexpressed during different stages of cell differentiation and development. This suggests an essential role for Hsp27 in the differentiation of tissues.

An affinity of high expression levels of different phosphorylated Hsp27 species and muscle/neurodegenerative diseases and various cancers was observed.[17] High expression levels possibly are in inverse relation with cell proliferation, metastasis, and resistance to chemotherapy.[18] High levels of Hsp27 were also found in sera of breast cancer patients;[19] therefore Hsp27 could be a potential diagnostic marker.

Function[edit]

The main function of Hsp27 is to provide thermotolerance in vivo, cytoprotection, and support of cell survival under stress conditions. More specialized functions of Hsp27 are manifold and complex. In vitro it acts as an ATP-independent chaperone by inhibiting protein aggregation and by stabilizing partially denatured proteins, which ensures refolding by the Hsp70-complex.

Hsp27 is also involved in the apoptotic signalling pathway. Hsp27 interacts with the outer mitochondrial membranes and interferes with the activation of cytochrome c/Apaf-1/dATP complex and therefore inhibits the activation of procaspase-9.[17] The phosphorylated form of Hsp27 inhibits Daxx apoptotic protein and prevents the association of Daxx with Fas and Ask1.[20]

A well documented function of Hsp27 is the interaction with actin and intermediate filaments. It prevents the formation of non-covalent filament/filament interactions of the intermediate filaments and protects actin filaments from fragmentation. It also preserves the focal contacts fixed at the cell membrane.[17]

Another function of Hsp27 is the activation of the proteasome. It speeds up the degradation of irreversibly denatured proteins and junkproteins by binding to ubiquitinated proteins and to the 26S proteasome. Hsp27 enhances the activation of the NF-κB pathway, that controls a lot of processes, such as cell growth and inflammatory and stress responses.[21] The cytoprotective properties of Hsp27 result from its ability to modulate reactive oxygen species and to raise glutathione levels.

Probably Hsp27 – among other chaperones – is involved in the process of cell differentiation.[22] Changes of Hsp27 levels were observed in Ehrlich ascite cells, embryonic stem cells, normal B-cells, B-lymphoma cells, osteoblasts, keratinocytes, neurons etc. The upregulation of Hsp27 correlates with the rate of phosphorylation and with an increase of large oligomers. It is possible that Hsp27 plays a crucial role in the termination of growth.

Interactions[edit]

Hsp27 has been shown to interact with:

References[edit]

  1. ^ Baranova, E. V.; Weeks, S. D.; Beelen, S.; Bukach, O. V.; Gusev, N. B.; Strelkov, S. V. (2011). "Three-Dimensional Structure of α-Crystallin Domain Dimers of Human Small Heat Shock Proteins HSPB1 and HSPB6". Journal of Molecular Biology 411 (1): 110–122. doi:10.1016/j.jmb.2011.05.024. PMID 21641913.  edit
  2. ^ Carper SW, Rocheleau TA, Storm FK (November 1990). "cDNA sequence of a human heat shock protein HSP27". Nucleic Acids Res. 18 (21): 6457. doi:10.1093/nar/18.21.6457. PMC 332574. PMID 2243808. 
  3. ^ Hunt CR, Goswami PC, Kozak CA (October 1997). "Assignment of the mouse Hsp25 and Hsp105 genes to the distal region of chromosome 5 by linkage analysis". Genomics 45 (2): 462–3. doi:10.1006/geno.1997.4973. PMID 9344682. 
  4. ^ a b Kim KK, Kim R, Kim SH (August 1998). "Crystal structure of a small heat-shock protein". Nature 394 (6693): 595–9. doi:10.1038/29106. PMID 9707123. 
  5. ^ a b Van Montfort R, Slingsby C, Vierling E (2001). "Structure and function of the small heat shock protein/alpha-crystallin family of molecular chaperones". Adv. Protein Chem. Advances in Protein Chemistry 59: 105–56. doi:10.1016/S0065-3233(01)59004-X. ISBN 9780120342594. PMID 11868270. 
  6. ^ a b c Gusev NB, Bogatcheva NV, Marston SB (May 2002). "Structure and properties of small heat shock proteins (sHsp) and their interaction with cytoskeleton proteins". Biochemistry Mosc. 67 (5): 511–9. doi:10.1023/A:1015549725819. PMID 12059769. 
  7. ^ Liao JH, Lee JS, Chiou SH (September 2002). "C-terminal lysine truncation increases thermostability and enhances chaperone-like function of porcine alphaB-crystallin". Biochem. Biophys. Res. Commun. 297 (2): 309–16. doi:10.1016/S0006-291X(02)02185-X. PMID 12237119. 
  8. ^ Lelj-Garolla B, Mauk AG (January 2005). "Self-association of a small heat shock protein". J. Mol. Biol. 345 (3): 631–42. doi:10.1016/j.jmb.2004.10.056. PMID 15581903. 
  9. ^ Lindner RA, Carver JA, Ehrnsperger M, Buchner J, Esposito G, Behlke J, Lutsch G, Kotlyarov A, Gaestel M (April 2000). "Mouse Hsp25, a small shock protein. The role of its C-terminal extension in oligomerization and chaperone action". Eur. J. Biochem. 267 (7): 1923–32. doi:10.1046/j.1432-1327.2000.01188.x. PMID 10727931. 
  10. ^ Haslbeck M (October 2002). "sHsps and their role in the chaperone network". Cell. Mol. Life Sci. 59 (10): 1649–57. doi:10.1007/PL00012492. PMID 12475175. 
  11. ^ a b Thériault JR, Lambert H, Chávez-Zobel AT, Charest G, Lavigne P, Landry J (May 2004). "Essential role of the NH2-terminal WD/EPF motif in the phosphorylation-activated protective function of mammalian Hsp27". J. Biol. Chem. 279 (22): 23463–71. doi:10.1074/jbc.M402325200. PMID 15033973. 
  12. ^ a b Ehrnsperger M, Lilie H, Gaestel M, Buchner J (May 1999). "The dynamics of Hsp25 quaternary structure. Structure and function of different oligomeric species". J. Biol. Chem. 274 (21): 14867–74. doi:10.1074/jbc.274.21.14867. PMID 10329686. 
  13. ^ a b Rogalla T, Ehrnsperger M, Preville X, Kotlyarov A, Lutsch G, Ducasse C, Paul C, Wieske M, Arrigo AP, Buchner J, Gaestel M (July 1999). "Regulation of Hsp27 oligomerization, chaperone function, and protective activity against oxidative stress/tumor necrosis factor alpha by phosphorylation". J. Biol. Chem. 274 (27): 18947–56. doi:10.1074/jbc.274.27.18947. PMID 10383393. 
  14. ^ Garrido C (May 2002). "Size matters: of the small HSP27 and its large oligomers". Cell Death Differ. 9 (5): 483–5. doi:10.1038/sj/cdd/4401005. PMID 11973606. 
  15. ^ Bruey JM, Paul C, Fromentin A, Hilpert S, Arrigo AP, Solary E, Garrido C (October 2000). "Differential regulation of HSP27 oligomerization in tumor cells grown in vitro and in vivo". Oncogene 19 (42): 4855–63. doi:10.1038/sj.onc.1203850. PMID 11039903. 
  16. ^ Gawlowski T, Stratmann B, Stork I, Engelbrecht B, Brodehl A, Niehaus K, Körfer R, Tschoepe D, Milting H. Heat shock protein 27 modification is increased in the human diabetic failing heart. Horm Metab Res. 2009 Aug;41(8):594-9. doi: 10.1055/s-0029-1216374. Epub 2009 Apr 21.PMID: 19384818 
  17. ^ a b c Sarto C, Binz PA, Mocarelli P (April 2000). "Heat shock proteins in human cancer". Electrophoresis 21 (6): 1218–26. doi:10.1002/(SICI)1522-2683(20000401)21:6<1218::AID-ELPS1218>3.0.CO;2-H. PMID 10786894. 
  18. ^ Vargas-Roig LM, Fanelli MA, López LA, Gago FE, Tello O, Aznar JC, Ciocca DR (1997). "Heat shock proteins and cell proliferation in human breast cancer biopsy samples". Cancer Detect. Prev. 21 (5): 441–51. PMID 9307847. 
  19. ^ Rui Z, Jian-Guo J, Yuan-Peng T, Hai P, Bing-Gen R (April 2003). "Use of serological proteomic methods to find biomarkers associated with breast cancer". Proteomics 3 (4): 433–9. doi:10.1002/pmic.200390058. PMID 12687611. 
  20. ^ Charette SJ, Lavoie JN, Lambert H, Landry J (October 2000). "Inhibition of Daxx-mediated apoptosis by heat shock protein 27". Mol. Cell. Biol. 20 (20): 7602–12. doi:10.1128/MCB.20.20.7602-7612.2000. PMC 86317. PMID 11003656. 
  21. ^ Parcellier A, Schmitt E, Gurbuxani S, Seigneurin-Berny D, Pance A, Chantôme A, Plenchette S, Khochbin S, Solary E, Garrido C (August 2003). "HSP27 is a ubiquitin-binding protein involved in I-kappaBalpha proteasomal degradation". Mol. Cell. Biol. 23 (16): 5790–802. doi:10.1128/MCB.23.16.5790-5802.2003. PMC 166315. PMID 12897149. 
  22. ^ Arrigo AP (February 2005). "In search of the molecular mechanism by which small stress proteins counteract apoptosis during cellular differentiation". J. Cell. Biochem. 94 (2): 241–6. doi:10.1002/jcb.20349. PMID 15546148. 
  23. ^ a b c Fu L, Liang JJ (February 2002). "Detection of protein-protein interactions among lens crystallins in a mammalian two-hybrid system assay". J. Biol. Chem. 277 (6): 4255–60. doi:10.1074/jbc.M110027200. PMID 11700327. 
  24. ^ Kato K, Shinohara H, Goto S, Inaguma Y, Morishita R, Asano T (April 1992). "Copurification of small heat shock protein with alpha B crystallin from human skeletal muscle". J. Biol. Chem. 267 (11): 7718–25. PMID 1560006. 
  25. ^ Sinsimer KS, Gratacós FM, Knapinska AM, Lu J, Krause CD, Wierzbowski AV, Maher LR, Scrudato S, Rivera YM, Gupta S, Turrin DK, De La Cruz MP, Pestka S, Brewer G (September 2008). "Chaperone Hsp27, a novel subunit of AUF1 protein complexes, functions in AU-rich element-mediated mRNA decay". Mol. Cell. Biol. 28 (17): 5223–37. doi:10.1128/MCB.00431-08. PMC 2519747. PMID 18573886. 
  26. ^ Sun X, Fontaine JM, Rest JS, Shelden EA, Welsh MJ, Benndorf R (January 2004). "Interaction of human HSP22 (HSPB8) with other small heat shock proteins". J. Biol. Chem. 279 (4): 2394–402. doi:10.1074/jbc.M311324200. PMID 14594798. 
  27. ^ Irobi J, Van Impe K, Seeman P, Jordanova A, Dierick I, Verpoorten N, Michalik A, De Vriendt E, Jacobs A, Van Gerwen V, Vennekens K, Mazanec R, Tournev I, Hilton-Jones D, Talbot K, Kremensky I, Van Den Bosch L, Robberecht W, Van Vandekerckhove J, Van Broeckhoven C, Gettemans J, De Jonghe P, Timmerman V (June 2004). "Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy". Nat. Genet. 36 (6): 597–601. doi:10.1038/ng1328. PMID 15122253. 
  28. ^ Jia Y, Ransom RF, Shibanuma M, Liu C, Welsh MJ, Smoyer WE (October 2001). "Identification and characterization of hic-5/ARA55 as an hsp27 binding protein". J. Biol. Chem. 276 (43): 39911–8. doi:10.1074/jbc.M103510200. PMID 11546764. 

External links[edit]