Site- specific [[Protein phosphorylation|Phosphorylationphosphorylation]] 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]], 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|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 be delay [[cell cycle]] progression in yeast and mammals by altering [[Cyclin 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 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|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=PMC6754304|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>
