The ''' Chaperonechaperone code''' refers to [[Post-translational modification|post-translational modifications ]] of molecular [[Chaperone (protein)|chaperones ]] that control protein folding. WhileWhilst the [[genetic code]] specifies how [[DNA ]] makes proteins, whileand the [[histone code]] rulesregulates genomichistone-DNA transactionsinteractions, the chaperone code controls how proteins are folded to produce a functional [[proteome]].<ref name=":0">{{Cite journal| lastlast1=Nitika|last2=Porter|first2=Corey M.|last3=Truman|first3=Andrew W.|last4=Truttmann|first4=Matthias C.|date=2020-07-31|title=Post-translational modifications of Hsp70 family proteins: Expanding the chaperone code |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397107/|journal=The Journal of Biological Chemistry|volume=295|issue=31|pages=10689–10708|doi=10.1074/jbc.REV120.011666|issn=0021-9258|pmc=7397107|pmid=32518165 |doi-access=free }}</ref><ref name=":1">{{Cite journal| lastlast1=Backe| firstfirst1=Sarah J.|last2=Sager|first2=Rebecca A.|last3=Woodford|first3=Mark R.|last4=Makedon|first4=Alan M.|last5=Mollapour|first5=Mehdi|date=2020-08-07|title=Post-translational modifications of Hsp90 and translating the chaperone code |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415980/|journal=The Journal of Biological Chemistry|volume=295|issue=32|pages=11099–11117|doi=10.1074/jbc.REV120.011833|issn=0021-9258|pmc=7415980|pmid=32527727 |doi-access=free }}</ref> ▼<!-- Please do not remove or change this AfD message until the discussion has been closed. -->
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▲The '''Chaperone code''' refers to modifications of molecular chaperones that control protein folding. While the [[genetic code]] specifies how DNA makes proteins, while the [[histone code]] rules genomic transactions, the chaperone code controls how proteins are folded to produce a functional [[proteome]].<ref>{{Cite journal|last=Nitika|last2=Porter|first2=Corey M.|last3=Truman|first3=Andrew W.|last4=Truttmann|first4=Matthias C.|date=2020-07-31|title=Post-translational modifications of Hsp70 family proteins: Expanding the chaperone code|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397107/|journal=The Journal of Biological Chemistry|volume=295|issue=31|pages=10689–10708|doi=10.1074/jbc.REV120.011666|issn=0021-9258|pmc=7397107|pmid=32518165}}</ref><ref>{{Cite journal|last=Backe|first=Sarah J.|last2=Sager|first2=Rebecca A.|last3=Woodford|first3=Mark R.|last4=Makedon|first4=Alan M.|last5=Mollapour|first5=Mehdi|date=2020-08-07|title=Post-translational modifications of Hsp90 and translating the chaperone code|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415980/|journal=The Journal of Biological Chemistry|volume=295|issue=32|pages=11099–11117|doi=10.1074/jbc.REV120.011833|issn=0021-9258|pmc=7415980|pmid=32527727}}</ref>
The chaperone code refers to the combinatorial array of [[Post-translational modification|post-translational modifications]] (enzymes add chemical modifications to amino acids that change their properties) - i—i.e. [[phosphorylation]], [[acetylation]], [[Ubiquitin|ubiquitination]], [[methylation]], etc - that.—that are added to [[molecular chaperones]] to modulate their activity. Molecular chaperones are proteins specialized in folding and unfolding of the other cellular proteins, and the assembly and dismantling of protein complexes. This is critical in the regulation of protein-protein interactions and many cellular functions. Because post-translational modifications are marks that can be added and removed rapidly, they provide an efficient mechanism to explain the plasticity observed in proteome organization during cell growth and development.
The chaperone code concept posits that combinations of post-translational modifications at the surface of chaperones, including phosphorylation, acetylation,<ref name=":0" /> methylation,<ref>{{Cite journal|last1=Jakobsson|first1=Magnus E.|last2=Moen|first2=Anders|last3=Bousset|first3=Luc|last4=Egge-Jacobsen|first4=Wolfgang|last5=Kernstock|first5=Stefan|last6=Melki|first6=Ronald|last7=Falnes|first7=Pål Ø.|date=2013-09-27|title=Identification and Characterization of a Novel Human Methyltransferase Modulating Hsp70 Protein Function through Lysine Methylation|journal=The Journal of Biological Chemistry|volume=288|issue=39|pages=27752–27763|doi=10.1074/jbc.M113.483248|issn=0021-9258|pmc=3784692|pmid=23921388|doi-access=free }}</ref> ubiquitination,<ref>{{Cite journal|last1=Kampinga|first1=Harm H.|last2=Craig|first2=Elizabeth A.|date=August 2010|title=The Hsp70 chaperone machinery: J-proteins as drivers of functional specificity|journal=Nature Reviews. Molecular Cell Biology|volume=11|issue=8|pages=579–592|doi=10.1038/nrm2941|issn=1471-0072|pmc=3003299|pmid=20651708}}</ref> control protein folding/unfolding and protein complex assembly/disassembly by modulating:
1) [[Substrate (chemistry)|chaperone-substrate]] affinity and specificity
2) chaperone ATPase and therefore its refolding activity
3) chaperone localization
The4) chaperone code concept posits that combinations of posttranslational modifications at the surface of chaperones, including phosphorylation, acetylation, methylation, ubiquitination, etc, control protein folding/unfolding and protein complex assembly/disassembly by stipulating substrate specificity, activity, subcellular localization and -co- factorchaperone bindinginteraction. <ref>{{cite journal |doi=10.1016/j.bbagrm.2013.02.010 |pmid=23459247 |pmc=4492711 |title=Regulation of molecular chaperones through post-translational modifications: Decrypting the chaperone code |journal=Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms |volume=1829 |issue=5 |pages=443–54 |year=2013 |last1=Cloutier |first1=Philippe |last2=Coulombe |first2=Benoit }}</ref><ref>{{cite journal |doi=10.1371/journal.pgen.1003210 |pmid=23349634 |pmc=3547847 |title=A Newly Uncovered Group of Distantly Related Lysine Methyltransferases Preferentially Interact with Molecular Chaperones to Regulate Their Activity |journal=PLOS Genetics |volume=9 |issue=1 |pages=e1003210 |year=2013 |last1=Cloutier |first1=Philippe |last2=Lavallée-Adam |first2=Mathieu |last3=Faubert |first3=Denis |last4=Blanchette |first4=Mathieu |last5=Coulombe |first5=Benoit |doi-access=free }}</ref> Because posttranslational modifications are marks that can be added and removed rapidly, they provide an efficient mechanism to explain the plasticity observed in proteome organization during cell growth and development.▼
== Levels of the Chaperone Code ==
The Chaperone code is incredibly complex with multiple layers of potential regulation. Studies of the chaperone code may include:
Level 1: Understanding the role and regulation of single PTMs on a single chaperone
Level 2: Cross-talk of different PTMs on a single amino acid or between PTMs on different amino acids (on a single chaperone)
Level 3: Understanding of why chaperone paralogs have different PTMs
Level 4: Cross-talk of PTMs between different chaperones i.e. between Hsp90 and Hsp70
Level 5: Understanding the role and regulation of single PTMs on a single co-chaperone molecule
▲The chaperone code concept posits that combinations of posttranslational modifications at the surface of chaperones, including phosphorylation, acetylation, methylation, ubiquitination, etc, control protein folding/unfolding and protein complex assembly/disassembly by stipulating substrate specificity, activity, subcellular localization and co-factor binding. <ref>{{cite journal |doi=10.1016/j.bbagrm.2013.02.010 |pmid=23459247 |pmc=4492711 |title=Regulation of molecular chaperones through post-translational modifications: Decrypting the chaperone code |journal=Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms |volume=1829 |issue=5 |pages=443–54 |year=2013 |last1=Cloutier |first1=Philippe |last2=Coulombe |first2=Benoit }}</ref><ref>{{cite journal |doi=10.1371/journal.pgen.1003210 |pmid=23349634 |pmc=3547847 |title=A Newly Uncovered Group of Distantly Related Lysine Methyltransferases Preferentially Interact with Molecular Chaperones to Regulate Their Activity |journal=PLOS Genetics |volume=9 |issue=1 |pages=e1003210 |year=2013 |last1=Cloutier |first1=Philippe |last2=Lavallée-Adam |first2=Mathieu |last3=Faubert |first3=Denis |last4=Blanchette |first4=Mathieu |last5=Coulombe |first5=Benoit }}</ref> Because posttranslational modifications are marks that can be added and removed rapidly, they provide an efficient mechanism to explain the plasticity observed in proteome organization during cell growth and development.
Level 6: Understanding the entire chaperone code-all the PTMs on all major chaperones, co-chaperones that control all aspects of life.
== Phosphorylation ==
PhosphorylationSite-specific [[Protein phosphorylation|phosphorylation]] of chaperone proteins can affect their activity. In some cases phosphorylation may disrupt the interaction with a co-chaperone protein thus negatively affecting its activity. In other instances it may promote the activation of particular chaperone targets (referred to as clients).<ref>{{Cite journal|last1=Woodford|first1=Mark R.|last2=Truman|first2=Andrew W.|last3=Dunn|first3=Diana M.|last4=Jensen|first4=Sandra M.|last5=Cotran|first5=Richard|last6=Bullard|first6=Renee|last7=Abouelleil|first7=Mourad|last8=Beebe|first8=Kristin|last9=Wolfgeher|first9=Donald|last10=Wierzbicki|first10=Sara|last11=Post|first11=Dawn E.|date=2016-02-02|title=Mps1 Mediated Phosphorylation of Hsp90 Confers Renal Cell Carcinoma Sensitivity and Selectivity to Hsp90 Inhibitors|journal=Cell Reports|volume=14|issue=4|pages=872–884|doi=10.1016/j.celrep.2015.12.084|issn=2211-1247|pmc=4887101|pmid=26804907}}</ref> Enzymes such as [[protein kinase A]], casein kinase 1 and 2 ([[Casein kinase 1|CK1]] and [[Casein kinase 2|CK2]]), and [[GSK3B|glycogen synthase kinase B]] serve as kinases for chaperone proteins.<ref name=":1" /> [[Hsp70|HSP70]], a major chaperone protein, was identified in 2012 as a hotspot of phospho-regulation. <ref>{{Cite journal|lastlast1=Beltrao|firstfirst1=Pedro|last2=Albanèse|first2=Véronique|last3=Kenner|first3=Lillian R.|last4=Swaney|first4=Danielle L.|last5=Burlingame|first5=Alma|last6=Villén|first6=Judit|last7=Lim|first7=Wendell A.|last8=Fraser|first8=James S.|last9=Frydman|first9=Judith|last10=Krogan|first10=Nevan J.|date=2012-07-20|title=Systematic Functional Prioritization of Protein Posttranslational Modifications|url=https://www.cell.com/cell/abstract/S0092-8674(12)00706-4 |journal=Cell|language=English|volume=150|issue=2|pages=413–425|doi=10.1016/j.cell.2012.05.036|issn=0092-8674|pmid=22817900|pmc=3404735}}</ref> Subsequently, phosphorylation of chaperone protein HSP70 by a cyclin dependent kinase was shown to be delay [[cell cycle]] progression in yeast and mammals by altering [[Cyclincyclin D1]] stability (a key regulator of the cell cycle). <ref>{{Cite journal|lastlast1=Truman|firstfirst1=Andrew W.|last2=Kristjansdottir|first2=Kolbrun|last3=Wolfgeher|first3=Donald|last4=Hasin|first4=Naushaba|last5=Polier|first5=Sigrun|last6=Zhang|first6=Hong|last7=Perrett|first7=Sarah|last8=Prodromou|first8=Chrisostomos|last9=Jones|first9=Gary W.|last10=Kron|first10=Stephen J.|date=2012-12-07|title=CDK-Dependent Hsp70 Phosphorylation Controls G1 Cyclin Abundance and Cell-Cycle Progression|urljournal=https:Cell|volume=151|issue=6|pages=1308–1318|doi=10.1016//wwwj.ncbicell.nlm2012.nih10.gov/051|issn=0092-8674|pmc=3778871|pmid=23217712}}</articles/PMC3778871ref> Phosphorylation of HSP90 (another major chaperone) at threonine 22, was shown to disrupt its interaction with co-chaperone proteins Aha1 and CD37 (interacting proteins required for function) and decrease its activity.<ref name=":1" /><ref>{{Cite journal|last1=Mollapour|first1=Mehdi|last2=Tsutsumi|first2=Shinji|last3=Truman|first3=Andrew W.|last4=Xu|first4=Wanping|last5=Vaughan|first5=Cara K.|last6=Beebe|first6=Kristin|last7=Konstantinova|first7=Anna|last8=Vourganti|first8=Srinivas|last9=Panaretou|first9=Barry|last10=Piper|first10=Peter W.|last11=Trepel|first11=Jane B.|date=2011-03-18|title=Threonine 22 phosphorylation attenuates Hsp90 interaction with co-chaperones and affects its chaperone activity|journal=Molecular Cell|volume=15141|issue=6|pages=1308–1318672–681|doi=10.1016/j.cellmolcel.20122011.02.011|issn=1097-2765|pmc=3062913|pmid=21419342}}</ref> Certain pathogenic bacteria may manipulate host chaperone phosphorylation through bacterial effectors to promote their survival. HoPBF1, a family of bacterial effector protein kinases, phosphorylates HSP90 at Serine 99 to dampen immunity.<ref>{{Cite journal|last1=Lopez|first1=Victor A.|last2=Park|first2=Brenden C.|last3=Nowak|first3=Dominika|last4=Sreelatha|first4=Anju|last5=Zembek|first5=Patrycja|last6=Fernandez|first6=Jessie|last7=Servage|first7=Kelly A.|last8=Gradowski|first8=Marcin|last9=Hennig|first9=Jacek|last10=Tomchick|first10=Diana R.|last11=Pawłowski|first11=Krzysztof|date=2019-09-19|title=A Bacterial Effector Mimics a Host HSP90 Client to Undermine Immunity|url= |journal=Cell|language=English|volume=179|issue=1|pages=205–218.e21|doi=10.0511016/j.cell.2019.08.020|issn=0092-8674|pmc=37788716754304|pmid=2321771231522888}}</ref>
== Methylation ==
Chaperone proteins are also regulated by methylation. This can occur through a conformational change (or a change in the structure of the protein), such that the interactions and activity of the protein are changed. <ref name=":1" /><ref>{{Cite journal|last1=Donlin|first1=Laura T.|last2=Andresen|first2=Christian|last3=Just|first3=Steffen|last4=Rudensky|first4=Eugene|last5=Pappas|first5=Christopher T.|last6=Kruger|first6=Martina|last7=Jacobs|first7=Erica Y.|last8=Unger|first8=Andreas|last9=Zieseniss|first9=Anke|last10=Dobenecker|first10=Marc-Werner|last11=Voelkel|first11=Tobias|date=2012-01-15|title=Smyd2 controls cytoplasmic lysine methylation of Hsp90 and myofilament organization|journal=Genes & Development|volume=26|issue=2|pages=114–119|doi=10.1101/gad.177758.111|issn=0890-9369|pmc=3273835|pmid=22241783}}</ref> For instance, the monomethylation of HSP90 lysine 616 by [[SMPD2|Smyd2]], and its reversal by [[KDM1A|LSD1]], regulate enzymatic activity of HSP90.<ref>{{Cite journal|last1=Abu-Farha|first1=Mohamed|last2=Lanouette|first2=Sylvain|last3=Elisma|first3=Fred|last4=Tremblay|first4=Véronique|last5=Butson|first5=Jeffery|last6=Figeys|first6=Daniel|last7=Couture|first7=Jean-François|date=October 2011|title=Proteomic analyses of the SMYD family interactomes identify HSP90 as a novel target for SMYD2|journal=Journal of Molecular Cell Biology|volume=3|issue=5|pages=301–308|doi=10.1093/jmcb/mjr025|issn=1759-4685|pmid=22028380|doi-access=free}}</ref><ref>{{Cite journal|last1=Rehn|first1=Alexandra|last2=Lawatscheck|first2=Jannis|last3=Jokisch|first3=Marie-Lena|last4=Mader|first4=Sophie L.|last5=Luo|first5=Qi|last6=Tippel|first6=Franziska|last7=Blank|first7=Birgit|last8=Richter|first8=Klaus|last9=Lang|first9=Kathrin|last10=Kaila|first10=Ville R. I.|last11=Buchner|first11=Johannes|date=May 2020|title=A methylated lysine is a switch point for conformational communication in the chaperone Hsp90|journal=Nature Communications|volume=11|issue=1|pages=1219|doi=10.1038/s41467-020-15048-8|issn=2041-1723|pmc=7057950|pmid=32139682|bibcode=2020NatCo..11.1219R}}</ref>
==References==
[[Category:Genetics]]
[[Category:Protein folding]]
[[Category:Methylation]]
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