Chaperones

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Chaperones are proteins that are involved in the folding and unfolding of other macromolecules. The word chaperone means 'giving protection' which implies the idea of preventing new proteins from misfolding. They exists both in prokaryotes and eukaryotes. Some chaperones are constitutively expressed in the system where as other chaperones are expressed only in response to an external stimulus or stress such as heat and therefore they are referred to as heat shock proteins. They are classified based on their structure, size, molecular weight and function in to several classes such as Hsp40s, Hsp60s Chaperonin, Hsp70s, Hsp90s such as 1am1, Hsp100s and small heat shock proteins like (alpha)-crystallin proteins. Various classes of molecular chaperones cooperate for the folding of the nascent polypeptide chains in the cyotplasm [1]. See also Heat Shock Proteins.

Contents

Function

Chaperones bind to the newly synthesized and unfolded proteins helping them acquire their properly folded 3D structure [2]. Besides, chaperones help in targeting the native proteins to their respective organelles [3][4]. The first identified chaperones were the histone chaperones that are continously involved in histone metabolism thus regulating genome function, stability and identity[5]. Many protozoan parasites such as Plasmodium falciparum requires these proteins for cytoprotection and targeting of nuclear encoded proteins to apicoplast required for necessary biosynthetic processes like fatty acid biosynthesis [6][7]. Chaperones actively participate in the maintenance of proteome integrity and protein homeostasis (proteostasis) which requires a syncrhonization in various chaperones tuning the process [8].

Disease

Chaperones are instrumental in protein folding processes. Alteration in this process may lead to protein aggregation and formation of inclusion bodies. Protein misfolding may result in various diseases such as Alzheimer [9], Parkinson [10], Familial amyotrophic lateral sclerosis [11], Huntington[12], Spinocerebellar ataxia 1, 2, 3 [13], Spinobulbar muscular atrophy [14] and ageing [15].

Relevance

Modulation of chaperone's expression is a new therapeutic approach for the neurodegenerative and other diseases arising from protein misfolding. There is a distinct network of chaperones and co chaperones that either directly influences the substrate proteins or in association with the protein degradation pathways such as the ubiquitin-proteasome-system or autophagy, results in the removal of completely misfolded and pathogenic proteins[16].

Structural highlights

Structurally, hsp70 have a N-terminal ATPase domain followed by a substrate binding domain with elongated C-terminal. These domains allosterically regulate the hsp70 functioning. In the 2D figure given below, panel A shows the structural organization of Hsp 70 indicating its various domains. ATP binding and hydrolysis regulates the affinity for substrate proteins which thereafter enhances ATP hydrolysis. Panel B predicts the various folded (green) and unfolded (red) regions in Hsp70.

Structural organization of Hsp70
Structural organization of Hsp70
Drag the structure with the mouse to rotate

References

  1. ↑ Kim YE, Hipp MS, Bracher A, Hayer-Hartl M, Hartl FU. Molecular chaperone functions in protein folding and proteostasis. Annu Rev Biochem. 2013;82:323-55. doi: 10.1146/annurev-biochem-060208-092442. PMID:23746257 doi:http://dx.doi.org/10.1146/annurev-biochem-060208-092442
  2. ↑ Ellis J. Proteins as molecular chaperones. Nature. 1987 Jul 30-Aug 5;328(6129):378-9. PMID:3112578 doi:http://dx.doi.org/10.1038/328378a0
  3. ↑ Deshaies RJ, Koch BD, Werner-Washburne M, Craig EA, Schekman R. A subfamily of stress proteins facilitates translocation of secretory and mitochondrial precursor polypeptides. Nature. 1988 Apr 28;332(6167):800-5. PMID:3282178 doi:http://dx.doi.org/10.1038/332800a0
  4. ↑ Halperin L, Jung J, Michalak M. The many functions of the endoplasmic reticulum chaperones and folding enzymes. IUBMB Life. 2014 May 19. doi: 10.1002/iub.1272. PMID:24839203 doi:http://dx.doi.org/10.1002/iub.1272
  5. ↑ Gurard-Levin ZA, Quivy JP, Almouzni G. Histone chaperones: assisting histone traffic and nucleosome dynamics. Annu Rev Biochem. 2014 Jun 2;83:487-517. doi:, 10.1146/annurev-biochem-060713-035536. PMID:24905786 doi:http://dx.doi.org/10.1146/annurev-biochem-060713-035536
  6. ↑ Misra G, Ramachandran R. Hsp70-1 from Plasmodium falciparum: protein stability, domain analysis and chaperone activity. Biophys Chem. 2009 Jun;142(1-3):55-64. doi: 10.1016/j.bpc.2009.03.006. Epub 2009 , Mar 16. PMID:19339102 doi:http://dx.doi.org/10.1016/j.bpc.2009.03.006
  7. ↑ Ramachandran R. Exploring the positional importance of aromatic residues and lysine in the interactions of peptides with the Plasmodium falciparum Hsp70-1. Biochim Biophys Acta. 2011 Mar;1814(3):457. doi: 10.1016/j.bbapap.2010.11.010. PMID:21316608 doi:http://dx.doi.org/10.1016/j.bbapap.2010.11.010
  8. ↑ Kim YE, Hipp MS, Bracher A, Hayer-Hartl M, Hartl FU. Molecular chaperone functions in protein folding and proteostasis. Annu Rev Biochem. 2013;82:323-55. doi: 10.1146/annurev-biochem-060208-092442. PMID:23746257 doi:http://dx.doi.org/10.1146/annurev-biochem-060208-092442
  9. ↑ Meriin AB, Sherman MY. Role of molecular chaperones in neurodegenerative disorders. Int J Hyperthermia. 2005 Aug;21(5):403-19. PMID:16048838 doi:http://dx.doi.org/10.1080/02656730500041871
  10. ↑ Winklhofer KF, Tatzelt J. The role of chaperones in Parkinson's disease and prion diseases. Handb Exp Pharmacol. 2006;(172):221-58. PMID:16610362
  11. ↑ Jain MR, Ge WW, Elkabes S, Li H. Amyotrophic lateral sclerosis: Protein chaperone dysfunction revealed by proteomic studies of animal models. Proteomics Clin Appl. 2008 May 1;2(5):670-684. PMID:19578526 doi:http://dx.doi.org/10.1002/prca.200780023
  12. ↑ Qi L, Zhang XD. Role of chaperone-mediated autophagy in degrading Huntington's disease-associated huntingtin protein. Acta Biochim Biophys Sin (Shanghai). 2014 Feb;46(2):83-91. doi:, 10.1093/abbs/gmt133. Epub 2013 Dec 8. PMID:24323530 doi:http://dx.doi.org/10.1093/abbs/gmt133
  13. ↑ Paulson H. Machado-Joseph disease/spinocerebellar ataxia type 3. Handb Clin Neurol. 2012;103:437-49. doi: 10.1016/B978-0-444-51892-7.00027-9. PMID:21827905 doi:http://dx.doi.org/10.1016/B978-0-444-51892-7.00027-9
  14. ↑ Bailey CK, Andriola IF, Kampinga HH, Merry DE. Molecular chaperones enhance the degradation of expanded polyglutamine repeat androgen receptor in a cellular model of spinal and bulbar muscular atrophy. Hum Mol Genet. 2002 Mar 1;11(5):515-23. doi: 10.1093/hmg/11.5.515. PMID:11875046 doi:http://dx.doi.org/10.1093/hmg/11.5.515
  15. ↑ Chaudhuri TK, Paul S. Protein-misfolding diseases and chaperone-based therapeutic approaches. FEBS J. 2006 Apr;273(7):1331-49. PMID:16689923 doi:http://dx.doi.org/10.1111/j.1742-4658.2006.05181.x
  16. ↑ Ebrahimi-Fakhari D, Saidi LJ, Wahlster L. Molecular chaperones and protein folding as therapeutic targets in Parkinson's disease and other synucleinopathies. Acta Neuropathol Commun. 2013 Dec 5;1(1):79. doi: 10.1186/2051-5960-1-79. PMID:24314025 doi:http://dx.doi.org/10.1186/2051-5960-1-79

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