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Hsp27




Heat shock 27kDa protein 1
Identifiers
Symbol(s) HSPB1; CMT2F; DKFZp586P1322; HS.76067; HSP27; HSP28; Hsp25
External IDs OMIM: 602195 MGI: 96240 Homologene: 1180
Orthologs
Human Mouse
Entrez 3315 15507
Ensembl ENSG00000106211 ENSMUSG00000004951
Uniprot P04792 Q545F4
Refseq NM_001540 (mRNA)
NP_001531 (protein)
NM_013560 (mRNA)
NP_038588 (protein)
Location Chr 7: 75.77 - 75.77 Mb Chr 5: 136.17 - 136.17 Mb
Pubmed search [1] [2]

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 and they take part in signal transduction.

Additional recommended knowledge

Contents

Structure of sHsps

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.[1][2]

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.[3]

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.[4] 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 [5] and in Hsp25Δ18.[6]

Oligomerization

The N-terminus with its WD/EPF-region is essential for the development of high molecular oligomers [7][8], 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 [3], which was shown with the proteins MjHSP16.5 from Methanocaldococcus jannaschii [1] and wheat Hsp16.9.[2] 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. [8][9][10] 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 [11], leads to the activation of MAPKAP kinases 2 and 3 which directly phosphorylate mammalian sHsps.[10] 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.[12]

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.[3] Therefore it is clear, that a formation of large aggregates takes place under heat shock. [9]

Cellular Localization

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. Probably it is essential for development in general: knock-out mice do not survive.

An affinity of high expression levels of different phosphorylated Hsp27 species and muscle/neurodegenerative diseases and various cancers was observed.[13] High expression levels possibly are in inverse relation with cell proliferation, metastasis, and resistance to chemotherapy.[14] High levels of Hsp27 were also found in sera of breast cancer patients [15]; therefore Hsp27 could be a potential diagnostical marker.

Functions

General functions are the thermotolerance in vivo, the cytoprotection, and the support of cell survival under stress conditions. Special functions 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.[13] The phosphorylated form of Hsp27 inhibits Daxx apoptotic protein and prevents the association of Daxx with Fas and Ask1.[16]

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 [13].

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.[17] 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.[18] Changes of Hsp27 levels were observed in Ehrlich ascite cells, embryonic stem cells, normal B-cells, B-lymphoma cells, osteoblasts, keratinocytes 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.

References

  1. ^ a b Kim KK, Kim R, Kim S. Crystal structure of a small heat shock protein. Nature. 394(6693):595-9. 1998.
  2. ^ a b Van Montfort R, Slingsby C, Vierling E. Structure and function of the small heat shock protein/alpha-crystallin family of molecular chaperones. Adv Protein Chem. 59:105-56. 2001.
  3. ^ a b c Gusev NB, Bogatcheva NV, Marston SB. Structure and properties of small heat shock proteins (sHsp) and their interaction with cytoskeleton proteins. Biochemistry (Mosc). 67(5):511-9. 2002.
  4. ^ Liao JH, Lee JS, Chiou SH. C-terminal lysine truncation increases thermostability and enhances chaperone-like function of porcine αB-crystallin. Biochem Biophys Res Commun. 297(2):309-16. 2002.
  5. ^ Lelj-Garolla B, Mauk AG. Self-association of a small heat shock protein. J Mol Biol. 345(3):631-42. 2005.
  6. ^ Lindner RA, Carver JA, Ehrnsperger M, Buchner J, Esposito G, Behlke J, Lutsch G, Kotlyarov A, Gaestel M. 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. 2000.
  7. ^ Haslbeck M. sHsps and their role in the chaperone network. Cell Mol Life Sci. 59(10):1649-57. 2002.
  8. ^ a b Theriault JR, Lambert H, Chavez-Zobel AT, Charest G, Lavigne P, Landry J. 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. 2004.
  9. ^ a b Ehrnsperger M, Lilie H, Gaestel M, Buchner J. The dynamics of Hsp25 quaternary structure. Structure and function of different oligomeric species. J Biol Chem. 274(21):14867-74. 1999.
  10. ^ a b Rogalla T, Ehrnsperger M, Preville X, Kotlyarov A, Lutsch G, Ducasse C, Paul C, Wieske M, Arrigo AP, Buchner J, Gaestel M. 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. 1999.
  11. ^ Garrido C. Size matters: of the small HSP27 and its large oligomers. Cell Death Differ. 9(5):483-5. 2002.
  12. ^ Bruey JM, Paul C, Fromentin A, Hilpert S, Arrigo AP, Solary E, Garrido C. Differential regulation of HSP27 oligomerization in tumor cells grown in vitro and in vivo. Oncogene. 19(42):4855-63. 2000.
  13. ^ a b c Sarto C, Binz PA, Mocarelli P. Heat shock proteins in human cancer. Electrophoresis. 21(6):1218-26. 2000.
  14. ^ Vargas-Roig LM, Fanelli MA, Lopez LA, Gago FE, Tello O, Aznar JC, Ciocca DR. Heat shock proteins and cell proliferation in human breast cancer biopsy samples. Cancer Detect Prev. 21(5):441-51. 1997.
  15. ^ Rui Z, Jian-Guo J, Yuan-Peng T, Hai P, Bing-Gen R. Use of serological proteomic methods to find biomarkers associated with breast cancer. Proteomics. 3(4):433-9. 2003.
  16. ^ Charette SJ, Lavoie JN, Lambert H, Landry J. Inhibition of Daxx-mediated apoptosis by heat shock protein 27. Mol Cell Biol. 20(20):7602-12. 2000.
  17. ^ Parcellier A, Schmitt E, Gurbuxani S, Seigneurin-Berny D, Pance A, Chantome A, Plenchette S, Khochbin S, Solary E, Garrido C. HSP27 is a ubiquitin-binding protein involved in I-kappaBalpha proteasomal degradation. Mol Cell Biol. 23(16):5790-802. 2003.
  18. ^ Arrigo AP. In search of the molecular mechanism by which small stress proteins counteract apoptosis during cellular differentiation. J Cell Biochem. 94(2):241-6. 2005.
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Hsp27". A list of authors is available in Wikipedia.
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