Editing Chaperone (protein) (section)

==Functions of molecular chaperones==
Many chaperones are [[heat shock protein]]s, that is, proteins [[gene expression|expressed]] in response to elevated temperatures or other cellular stresses.<ref>{{cite journal | vauthors = Ellis RJ, van der Vies SM | title = Molecular chaperones | journal = Annual Review of Biochemistry | volume = 60 | pages = 321–347 | year = 1991 | pmid = 1679318 | doi = 10.1146/annurev.bi.60.070191.001541 }}</ref> Heat shock protein chaperones are classified based on their observed molecular weights into Hsp60, [[Hsp70]], Hsp90, Hsp104, and small Hsps.<ref>{{cite journal | vauthors = Bascos NA, Landry SJ | title = A History of Molecular Chaperone Structures in the Protein Data Bank | journal = International Journal of Molecular Sciences | volume = 20 | issue = 24 | pages = 6195 | date = December 2019 | pmid = 31817979 | pmc = 6940948 | doi = 10.3390/ijms20246195 | doi-access = free }}</ref> The Hsp60 family of protein chaperones are termed [[chaperonin]]s, and are characterized by a stacked double-ring structure and are found in prokaryotes, in the cytosol of eukaryotes, and in mitochondria.

Some chaperone systems work as [[foldase]]s: they support the folding of proteins in an ATP-dependent manner (for example, the [[GroEL]]/[[GroES]] or the [[DnaK]]/[[DnaJ]]/[[GrpE]] system). Although most newly synthesized proteins can fold in absence of chaperones, a minority strictly requires them for the same. Other chaperones work as [[holdase]]s: they bind folding intermediates to prevent their aggregation, for example [[DnaJ]] or [[Hsp33]].<ref>{{cite journal | vauthors = Hoffmann JH, Linke K, Graf PC, Lilie H, Jakob U | title = Identification of a redox-regulated chaperone network | journal = The EMBO Journal | volume = 23 | issue = 1 | pages = 160–8 | date = January 2004 | pmid = 14685279 | pmc = 1271656 | doi = 10.1038/sj.emboj.7600016 }}</ref>
Chaperones can also work as disaggregases, which interact with aberrant protein assemblies and revert them to monomers.<ref>{{cite journal | vauthors = Nillegoda NB, Kirstein J, Szlachcic A, Berynskyy M, Stank A, Stengel F, Arnsburg K, Gao X, Scior A, Aebersold R, Guilbride DL, Wade RC, Morimoto RI, Mayer MP, Bukau B | display-authors = 6 | title = Crucial HSP70 co-chaperone complex unlocks metazoan protein disaggregation | journal = Nature | volume = 524 | issue = 7564 | pages = 247–51 | date = August 2015 | pmid = 26245380 | pmc = 4830470 | doi = 10.1038/nature14884 | bibcode = 2015Natur.524..247N }}</ref> Some chaperones can assist in [[protein degradation]], leading proteins to [[protease]] systems, such as the [[ubiquitin-proteasome system]] in [[eukaryotes]].<ref>{{cite journal | vauthors = Balchin D, Hayer-Hartl M, Hartl FU | title = In vivo aspects of protein folding and quality control | journal = Science | volume = 353 | issue = 6294 | pages = aac4354 | date = July 2016 | pmid = 27365453 | doi = 10.1126/science.aac4354 | hdl = 11858/00-001M-0000-002B-0856-C | s2cid = 5174431 | hdl-access = free }}</ref> Chaperone proteins participate in the folding of over half of all mammalian proteins.{{citation needed|date=February 2022}}

[[Macromolecular crowding]] may be important in chaperone function. The crowded environment of the [[cytosol]] can accelerate the folding process, since a compact folded protein will occupy less volume than an unfolded protein chain.<ref>{{cite journal | vauthors = van den Berg B, Wain R, Dobson CM, Ellis RJ | title = Macromolecular crowding perturbs protein refolding kinetics: implications for folding inside the cell | journal = The EMBO Journal | volume = 19 | issue = 15 | pages = 3870–5 | date = August 2000 | pmid = 10921869 | pmc = 306593 | doi = 10.1093/emboj/19.15.3870 }}</ref> However, crowding can reduce the yield of correctly folded protein by increasing [[protein aggregation]].<ref>{{cite journal | vauthors = van den Berg B, Ellis RJ, Dobson CM | title = Effects of macromolecular crowding on protein folding and aggregation | journal = The EMBO Journal | volume = 18 | issue = 24 | pages = 6927–33 | date = December 1999 | pmid = 10601015 | pmc = 1171756 | doi = 10.1093/emboj/18.24.6927 }}</ref><ref>{{cite journal | vauthors = Ellis RJ, Minton AP | title = Protein aggregation in crowded environments | journal = Biological Chemistry | volume = 387 | issue = 5 | pages = 485–97 | date = May 2006 | pmid = 16740119 | doi = 10.1515/BC.2006.064 | s2cid = 7336464 }}</ref> Crowding may also increase the effectiveness of the chaperone proteins such as [[GroEL]],<ref>{{cite journal | vauthors = Martin J, Hartl FU | title = The effect of macromolecular crowding on chaperonin-mediated protein folding | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 4 | pages = 1107–12 | date = February 1997 | pmid = 9037014 | pmc = 19752 | doi = 10.1073/pnas.94.4.1107 | bibcode = 1997PNAS...94.1107M | doi-access = free }}</ref> which could counteract this reduction in folding efficiency.<ref>{{cite book |author=Ellis RJ |title=Molecular Aspects of the Stress Response: Chaperones, Membranes and Networks |chapter=Protein Misassembly |volume=594 |pages=[https://archive.org/details/molecularaspects00pete/page/1 1–13] |year=2007 |pmid=17205670 |doi=10.1007/978-0-387-39975-1_1 |series=Advances in Experimental Medicine and Biology |isbn=978-0-387-39974-4 |url-access=registration |url=https://archive.org/details/molecularaspects00pete/page/1 |publisher=New York, N.Y.: Sprinter Science+Business Media, LLC; Austin, Tex.: Landes Bioscience/Eurekah.com }}</ref> Some highly specific 'steric chaperones' convey unique structural information onto proteins, which cannot be folded spontaneously. Such proteins violate [[Anfinsen's dogma]],<ref>{{cite journal |vauthors=Pauwels K, Van Molle I, Tommassen J, Van Gelder P |date=May 2007 |title=Chaperoning Anfinsen: the steric foldases |url=http://ultr23.vub.ac.be/ultr/pub/pdfs/290.pdf |url-status=dead |journal=Molecular Microbiology |volume=64 |issue=4 |pages=917–22 |doi=10.1111/j.1365-2958.2007.05718.x |pmid=17501917 |archive-url=https://web.archive.org/web/20120523130904/http://ultr23.vub.ac.be/ultr/pub/pdfs/290.pdf |archive-date=2012-05-23 |s2cid=6435829}}</ref> requiring [[protein dynamics]] to fold correctly.

Other types of chaperones are involved in transport across [[biological membrane|membranes]], for example membranes of the [[mitochondria]] and [[endoplasmic reticulum]] (ER) in [[eukaryote]]s. A [[bacterial]] translocation-specific chaperone [[Type II secretion system|SecB]] maintains newly synthesized [[Protein precursor|precursor]] [[polypeptide chain]]s in a [[Protein targeting|translocation]]-competent ([[Denaturation (biochemistry)#Background|generally unfolded]]) state and guides them to the [[translocon]].<ref name="pmid16194224">{{cite journal | vauthors = Zhou J, Xu Z | title = The structural view of bacterial translocation-specific chaperone SecB: implications for function | journal = Molecular Microbiology | volume = 58 | issue = 2 | pages = 349–57 | date = October 2005 | pmid = 16194224 | doi = 10.1111/j.1365-2958.2005.04842.x | url = https://deepblue.lib.umich.edu/bitstream/2027.42/74325/1/j.1365-2958.2005.04842.x.pdf | hdl = 2027.42/74325 | s2cid = 33227532 | hdl-access = free }}</ref>

New functions for chaperones continue to be discovered, such as [[bacterial adhesin]] activity, induction of aggregation towards non-amyloid aggregates,<ref name="pmid22065637">{{cite journal | vauthors = Specht S, Miller SB, Mogk A, Bukau B | title = Hsp42 is required for sequestration of protein aggregates into deposition sites in Saccharomyces cerevisiae | journal = J. Cell Biol. | volume = 195 | issue = 4 | pages = 617–29 | date = 14 November 2011 | pmid = 22065637 | pmc = 3257523 | doi =     10.1083/jcb.201106037 }}</ref> suppression of toxic protein oligomers via their clustering,<ref name="pmid21670152">{{cite journal | vauthors = Ojha J, Masilamoni G, Dunlap D, Udoff RA, Cashikar AG | title = Sequestration of toxic oligomers by HspB1 as a cytoprotective mechanism | journal = Mol. Cell. Biol. | volume = 31 | issue = 15 | pages = 3146–57 | date = August 2011 | pmid = 21670152 | pmc = 3147607 | doi = 10.1128/MCB.01187-10 }}</ref><ref name="pmid22802614">{{cite journal | vauthors = Mannini B, Cascella R, Zampagni M, van Waarde-Verhagen M, Meehan S, Roodveldt C, Campioni S, Boninsegna M, Penco A, Relini A, Kampinga HH, Dobson CM, Wilson MR, Cecchi C, Chiti F | title = Molecular mechanisms used by chaperones to reduce the toxicity of aberrant protein oligomers | journal = Proc. Natl. Acad. Sci. USA | volume = 109 | issue = 31 | pages = 12479–84 | date = 31 July 2012 | pmid = 22802614 | pmc = 3411936 | doi = 10.1073/pnas.1117799109 | bibcode = 2012PNAS..10912479M | doi-access = free }}</ref> and in responding to diseases linked to protein aggregation<ref name="pmid25771456">{{cite journal | vauthors = Sadigh-Eteghad S, Majdi A, Talebi M, Mahmoudi J, Babri S | title = Regulation of nicotinic acetylcholine receptors in Alzheimer׳s disease: a possible role of chaperones | journal = European Journal of Pharmacology | volume = 755 | pages = 34–41 | date = May 2015 | pmid = 25771456 | doi = 10.1016/j.ejphar.2015.02.047 | s2cid = 31929001 }}</ref> and cancer maintenance.<ref>{{cite journal | vauthors = Salamanca HH, Antonyak MA, Cerione RA, Shi H, Lis JT | title = Inhibiting heat shock factor 1 in human cancer cells with a potent RNA aptamer | journal = PLOS ONE | volume = 9 | issue = 5 | pages = e96330 | year = 2014 | pmid = 24800749 | pmc = 4011729 | doi = 10.1371/journal.pone.0096330 | bibcode = 2014PLoSO...996330S | doi-access = free }}</ref>