Editing Protein folding (section)

==== Chaperones ====
[[File:PDB 1gme EBI.jpg|thumb|Example of a small eukaryotic [[heat shock protein]]]]

[[Chaperone (protein)|Molecular chaperones]] are a class of proteins that aid in the correct folding of other proteins ''[[in vivo]]''. Chaperones exist in all cellular compartments and interact with the polypeptide chain in order to allow the native three-dimensional conformation of the protein to form; however, chaperones themselves are not included in the final structure of the protein they are assisting in.<ref name="Dobson_2003" /> Chaperones may assist in folding even when the nascent polypeptide is being synthesized by the ribosome.<ref name="Hartl_1996" /> Molecular chaperones operate by binding to stabilize an otherwise unstable structure of a protein in its folding pathway, but chaperones do not contain the necessary information to know the correct native structure of the protein they are aiding; rather, chaperones work by preventing incorrect folding conformations.<ref name="Hartl_1996">{{cite journal | vauthors = Hartl FU | title = Molecular chaperones in cellular protein folding | journal = Nature | volume = 381 | issue = 6583 | pages = 571–9 | date = June 1996 | pmid = 8637592 | doi = 10.1038/381571a0 | bibcode = 1996Natur.381..571H | s2cid = 4347271 }}</ref> In this way, chaperones do not actually increase the rate of individual steps involved in the folding pathway toward the native structure; instead, they work by reducing possible unwanted aggregations of the polypeptide chain that might otherwise slow down the search for the proper intermediate and they provide a more efficient pathway for the polypeptide chain to assume the correct conformations.<ref name="Dobson_2003" /> Chaperones are not to be confused with folding [[Catalysis|catalyst]] proteins, which catalyze chemical reactions responsible for slow steps in folding pathways. Examples of folding catalysts are protein [[disulfide isomerase]]s and [[peptidyl-prolyl isomerase]]s that may be involved in formation of [[disulfide bond]]s or interconversion between cis and trans stereoisomers of peptide group.<ref name="Hartl_1996" /> Chaperones are shown to be critical in the process of protein folding ''in vivo'' because they provide the protein with the aid needed to assume its proper alignments and conformations efficiently enough to become "biologically relevant".<ref name="Hartl_2011">{{cite journal | vauthors = Hartl FU, Bracher A, Hayer-Hartl M | title = Molecular chaperones in protein folding and proteostasis | journal = Nature | volume = 475 | issue = 7356 | pages = 324–32 | date = July 2011 | pmid = 21776078 | doi = 10.1038/nature10317 | s2cid = 4337671 }}</ref> This means that the polypeptide chain could theoretically fold into its native structure without the aid of chaperones, as demonstrated by protein folding experiments conducted ''[[in vitro]]'';<ref name="Hartl_2011" /> however, this process proves to be too inefficient or too slow to exist in biological systems; therefore, chaperones are necessary for protein folding ''in vivo.'' Along with its role in aiding native structure formation, chaperones are shown to be involved in various roles such as protein transport, degradation, and even allow [[Denaturation (biochemistry)|denatured proteins]] exposed to certain external denaturant factors an opportunity to refold into their correct native structures.<ref>{{cite journal | vauthors = Kim YE, Hipp MS, Bracher A, Hayer-Hartl M, Hartl FU | title = Molecular chaperone functions in protein folding and proteostasis | journal = Annual Review of Biochemistry | volume = 82 | pages = 323–55 | year = 2013 | pmid = 23746257 | doi = 10.1146/annurev-biochem-060208-092442 }}</ref>

A fully denatured protein lacks both tertiary and secondary structure, and exists as a so-called [[random coil]]. Under certain conditions some proteins can refold; however, in many cases, denaturation is irreversible.<ref name="Shortle">{{cite journal | vauthors = Shortle D | title = The denatured state (the other half of the folding equation) and its role in protein stability | journal = FASEB Journal | volume = 10 | issue = 1 | pages = 27–34 | date = January 1996 | pmid = 8566543 | doi = 10.1096/fasebj.10.1.8566543 | doi-access = free | s2cid = 24066207 }}</ref> Cells sometimes protect their proteins against the denaturing influence of heat with [[enzyme]]s known as [[heat shock protein]]s (a type of chaperone), which assist other proteins both in folding and in remaining folded.  [[Heat shock protein]]s have been found in all species examined, from [[bacteria]] to humans, suggesting that they evolved very early and have an important function.  Some proteins never fold in cells at all except with the assistance of chaperones which either isolate individual proteins so that their folding is not interrupted by interactions with other proteins or help to unfold misfolded proteins, allowing them to refold into the correct native structure.<ref name="Lee_2005">{{cite journal | vauthors = Lee S, Tsai FT | title = Molecular chaperones in protein quality control | journal = Journal of Biochemistry and Molecular Biology | volume = 38 | issue = 3 | pages = 259–65 | year = 2005 | pmid = 15943899 | doi = 10.5483/BMBRep.2005.38.3.259 | doi-access = free }}</ref> This function is crucial to prevent the risk of [[precipitation (chemistry)|precipitation]] into [[insoluble]] amorphous aggregates. The external factors involved in protein denaturation or disruption of the native state include temperature, external fields (electric, magnetic),<ref name="ojeda">{{cite journal | vauthors = Ojeda-May P, Garcia ME | title = Electric field-driven disruption of a native beta-sheet protein conformation and generation of a helix-structure | journal = Biophysical Journal | volume = 99 | issue = 2 | pages = 595–9 | date = July 2010 | pmid = 20643079 | pmc = 2905109 | doi = 10.1016/j.bpj.2010.04.040 | bibcode = 2010BpJ....99..595O }}</ref> molecular crowding,<ref name="berg">{{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> and even the limitation of space (i.e. confinement), which can have a big influence on the folding of proteins.<ref>{{cite journal | vauthors = Ellis RJ | title = Molecular chaperones: assisting assembly in addition to folding | journal = Trends in Biochemical Sciences | volume = 31 | issue = 7 | pages = 395–401 | date = July 2006 | pmid = 16716593 | doi = 10.1016/j.tibs.2006.05.001 }}</ref> High concentrations of [[solutes]], extremes of [[pH]], mechanical forces, and the presence of chemical denaturants can contribute to protein denaturation, as well. These individual factors are categorized together as stresses. Chaperones are shown to exist in increasing concentrations during times of cellular stress and help the proper folding of emerging proteins as well as denatured or misfolded ones.<ref name="Dobson_2003" />

Under some conditions proteins will not fold into their biochemically functional forms. Temperatures above or below the range that cells tend to live in will cause [[Thermostability|thermally unstable]] proteins to unfold or denature (this is why boiling makes an [[Egg white#Denaturation|egg white]] turn opaque). Protein thermal stability is far from constant, however; for example, [[hyperthermophiles|hyperthermophilic bacteria]] have been found that grow at temperatures as high as 122&nbsp;°C,<ref>{{cite journal | vauthors = Takai K, Nakamura K, Toki T, Tsunogai U, Miyazaki M, Miyazaki J, Hirayama H, Nakagawa S, Nunoura T, Horikoshi K | title = Cell proliferation at 122 degrees C and isotopically heavy CH4 production by a hyperthermophilic methanogen under high-pressure cultivation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 31 | pages = 10949–54 | date = August 2008 | pmid = 18664583 | pmc = 2490668 | doi = 10.1073/pnas.0712334105 | bibcode = 2008PNAS..10510949T | doi-access = free }}</ref> which of course requires that their full complement of vital proteins and protein assemblies be stable at that temperature or above.

The bacterium ''[[E. coli]]'' is the host for [[bacteriophage T4]], and the phage encoded gp31 protein ({{UniProt|P17313}}) appears to be structurally and functionally homologous to ''E. coli'' chaperone protein [[GroES]] and able to substitute for it in the assembly of bacteriophage T4 [[virus]] particles during infection.<ref name = Marusich1998>{{cite journal |last1=Marusich |first1=EI |last2=Kurochkina |first2=LP |last3=Mesyanzhinov |first3=VV |title=Chaperones in bacteriophage T4 assembly |journal=Biochemistry. Biokhimiia |date=April 1998 |volume=63 |issue=4 |pages=399–406 |pmid=9556522 |url=http://www.protein.bio.msu.ru/biokhimiya/contents/v63/full/63040473.html }}</ref> Like GroES, gp31 forms a stable complex with [[GroEL]] chaperonin that is absolutely necessary for the folding and assembly in vivo of the bacteriophage T4 major capsid protein gp23.<ref name = Marusich1998/>