Chaperone code: Difference between revisions

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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 posttranslationalpost-translational modifications (enzymes add chemical modifications to amino acids that change their properties) - i.e. phosphorylation, acetylation, ubiquitination, methylation, etc - that targetare 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,. therebyThis orchestratingis thecritical dynamic organization ofin the proteome. As a consequence, a limited numberregulation of chaperonesprotein-protein mustinteractions beand ablemany to act on a very large number of substrates in a highly regulatedcellular mannerfunctions.

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. This conclusion emerges from the analysis of nearly two hundred reports in the literature,<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> including a key article published in 2013 reporting on the discovery of a novel family of methyltransferases that preferentially target and regulate molecular chaperones.<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 ==

Phosphorylation of chaperone proteins can affect their activity. 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|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 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|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}}</ref>

A large number of diseases, including degenerative neuromuscular disorders and cancer, are associated with dysfunction of molecular chaperones.

==References==