Chaperone code: Difference between revisions

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{{notability|date=March 2013}}

The '''Chaperone code''' refers to modifications of molecular [[Chaperone (protein)|chaperones]] that control protein folding. Whilst the [[genetic code]] specifies how [[DNA]] makes proteins, and the [[histone code]] regulates histone-DNA interactions, the chaperone code controls how proteins are folded to produce a functional [[proteome]].<ref name=":0">{{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 name=":1">{{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.

The chaperone code concept posits that combinations of posttranslational modifications at the surface of chaperones, including phosphorylation, acetylation<ref name=":0" />, methylation,<ref>{{Cite journal|last=Jakobsson|first=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|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784692/|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}}</ref> ubiquitination,<ref>{{Cite journal|last=Kampinga|first=Harm H.|last2=Craig|first2=Elizabeth A.|date=August 2010|title=The Hsp70 chaperone machinery: J-proteins as drivers of functional specificity|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3003299/|journal=Nature reviews. Molecular cell biology|volume=11|issue=8|pages=579–592|doi=10.1038/nrm2941|issn=1471-0072|pmc=3003299|pmid=20651708|via=}}</ref> control protein folding/unfolding and protein complex assembly/disassembly by regulation of [[Substrate (chemistry)|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.

== Phosphorylation ==

Site- 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|last=Woodford|first=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|url=https://pubmed.ncbi.nlm.nih.gov/26804907/|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]], Caseincasein Kinasekinase 1 and 2 ([[Casein kinase 1|CK1]] and [[Casein kinase 2|CK2]]), and [[GSK3B|Glycogenglycogen 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|last=Beltrao|first=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}}</ref> Subsequently, phosphorylation of chaperone protein HSP70 by a cyclin dependent kinase was shown to delay [[cell cycle]] progression in yeast and mammals by altering [[Cyclincyclin D1]] stability (a key regulator of the cell cycle). <ref>{{Cite journal|last=Truman|first=Andrew|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|last10=Kron|first10=Stephen|date=2012-12-07|title=CDK-Dependent Hsp70 Phosphorylation Controls G1 Cyclin Abundance and Cell-Cycle Progression|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3778871/|journal=Cell|volume=151|issue=6|pages=1308–1318|doi=10.1016/j.cell.2012.10.051|issn=0092-8674|pmc=3778871|pmid=23217712|via=}}</ref> Phosphorylation of HSP90 (another major chaperone) at Threoninethreonine 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|last=Mollapour|first=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|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062913/|journal=Molecular cell|volume=41|issue=6|pages=672–681|doi=10.1016/j.molcel.2011.02.011|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|last=Lopez|first=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=https://www.cell.com/cell/abstract/S0092-8674(19)30908-0|journal=Cell|language=English|volume=179|issue=1|pages=205–218.e21|doi=10.1016/j.cell.2019.08.020|issn=0092-8674|pmc=6754304|pmid=31522888}}</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|last=Donlin|first=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|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3273835/|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|last=Abu-Farha|first=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|url=https://pubmed.ncbi.nlm.nih.gov/22028380/|journal=Journal of Molecular Cell Biology|volume=3|issue=5|pages=301–308|doi=10.1093/jmcb/mjr025|issn=1759-4685|pmid=22028380|via=}}</ref><ref>{{Cite journal|last=Rehn|first=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|url=https://pubmed.ncbi.nlm.nih.gov/32139682/|journal=Nature Communications|volume=11|issue=1|pages=1219|doi=10.1038/s41467-020-15048-8|issn=2041-1723|pmc=7057950|pmid=32139682|via=}}</ref>

==References==