Chaperone code

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The chaperone code refers to post-translational modifications of molecular 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. [1] [2]

Contents

The chaperone code refers to the combinatorial array of post-translational modifications (enzymes add chemical modifications to amino acids that change their properties) —i.e. phosphorylation, acetylation, ubiquitination, methylation, etc.—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, [1] methylation, [3] ubiquitination, [4] control protein folding/unfolding and protein complex assembly/disassembly by modulating:

1) chaperone-substrate affinity and specificity

2) chaperone ATPase and therefore its refolding activity

3) chaperone localization

4) chaperone-co-chaperone interaction. [5] [6]

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

Level 6: Understanding the entire chaperone code-all the PTMs on all major chaperones, co-chaperones that control all aspects of life.

Phosphorylation

Site-specific 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). [7] Enzymes such as protein kinase A, casein kinase 1 and 2 (CK1 and CK2), and glycogen synthase kinase B serve as kinases for chaperone proteins. [2] HSP70, a major chaperone protein, was identified in 2012 as a hotspot of phospho-regulation. [8] Subsequently, phosphorylation of chaperone protein HSP70 by a cyclin dependent kinase was shown to delay cell cycle progression in yeast and mammals by altering cyclin D1 stability (a key regulator of the cell cycle). [9] 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. [2] [10] 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. [11]

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. [2] [12] For instance, the monomethylation of HSP90 lysine 616 by Smyd2, and its reversal by LSD1, regulate enzymatic activity of HSP90. [13] [14]

Related Research Articles

<span class="mw-page-title-main">Histone</span> Family proteins package and order the DNA into structural units called nucleosomes.

In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wrapped into 30-nanometer fibers that form tightly packed chromatin. Histones prevent DNA from becoming tangled and protect it from DNA damage. In addition, histones play important roles in gene regulation and DNA replication. Without histones, unwound DNA in chromosomes would be very long. For example, each human cell has about 1.8 meters of DNA if completely stretched out; however, when wound about histones, this length is reduced to about 90 micrometers (0.09 mm) of 30 nm diameter chromatin fibers.

<span class="mw-page-title-main">Hsp70</span> Family of heat shock proteins

The 70 kilodalton heat shock proteins are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms. Intracellularly localized Hsp70s are an important part of the cell's machinery for protein folding, performing chaperoning functions, and helping to protect cells from the adverse effects of physiological stresses. Additionally, membrane-bound Hsp70s have been identified as a potential target for cancer therapies and their extracellularly localized counterparts have been identified as having both membrane-bound and membrane-free structures.

<span class="mw-page-title-main">Heat shock protein 90kDa alpha (cytosolic), member A1</span> Protein-coding gene in the species Homo sapiens

Heat shock protein HSP 90-alpha is a protein that in humans is encoded by the HSP90AA1 gene.

<span class="mw-page-title-main">HSPA1B</span> Human gene

Human gene HSPA1B is an intron-less gene which encodes for the heat shock protein HSP70-2, a member of the Hsp70 family of proteins. The gene is located in the major histocompatibility complex, on the short arm of chromosome 6, in a cluster with two paralogous genes, HSPA1A and HSPA1L. HSPA1A and HSPA1B produce nearly identical proteins because the few differences in their DNA sequences are almost exclusively synonymous substitutions or in the three prime untranslated region, heat shock 70kDa protein 1A, from HSPA1A, and heat shock 70kDa protein 1B, from HSPA1B. A third, more modified paralog to these genes exists in the same region, HSPA1L, which shares a 90% homology with the other two.

<span class="mw-page-title-main">HSF1</span> Protein-coding gene in the species Homo sapiens

Heat shock factor 1 (HSF1) is a protein that in humans is encoded by the HSF1 gene. HSF1 is highly conserved in eukaryotes and is the primary mediator of transcriptional responses to proteotoxic stress with important roles in non-stress regulation such as development and metabolism.

<span class="mw-page-title-main">CDC37</span> Protein-coding gene in the species Homo sapiens

Hsp90 co-chaperone Cdc37 is a protein that in humans is encoded by the CDC37 gene. This protein is highly similar to Cdc 37, a cell division cycle control protein of Saccharomyces cerevisiae. This protein is a HSP90 Co-chaperone with specific function in cell signal transduction. It has been shown to form complex with Hsp90 and a variety of protein kinases including CDK4, CDK6, SRC, RAF1, MOK, as well as eIF-2 alpha kinases. It is thought to play a critical role in directing Hsp90 to its target kinases.

<span class="mw-page-title-main">HSP90AB1</span> Protein-coding gene in the species Homo sapiens

Heat shock protein HSP 90-beta also called HSP90beta is a protein that in humans is encoded by the HSP90AB1 gene.

<span class="mw-page-title-main">FNIP1</span> Protein-coding gene in the species Homo sapiens

Folliculin-interacting protein 1 (FNIP1) functions as a co-chaperone which inhibits the ATPase activity of the chaperone Hsp90 and decelerates its chaperone cycle. FNIP1 acts as a scaffold to load FLCN onto Hsp90. FNIP1 is also involved in chaperoning of both kinase and non-kinase clients.

H3K27ac is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates acetylation of the lysine residue at N-terminal position 27 of the histone H3 protein.

H2BK5ac is an epigenetic modification to the DNA packaging protein Histone H2B. It is a mark that indicates the acetylation at the 5th lysine residue of the histone H2B protein. H2BK5ac is involved in maintaining stem cells and colon cancer.

H4K16ac is an epigenetic modification to the DNA packaging protein Histone H4. It is a mark that indicates the acetylation at the 16th lysine residue of the histone H4 protein.

H4K5ac is an epigenetic modification to the DNA packaging protein histone H4. It is a mark that indicates the acetylation at the 5th lysine residue of the histone H4 protein. H4K5 is the closest lysine residue to the N-terminal tail of histone H4. It is enriched at the transcription start site (TSS) and along gene bodies. Acetylation of histone H4K5 and H4K12ac is enriched at centromeres.

H4K8ac, representing an epigenetic modification to the DNA packaging protein histone H4, is a mark indicating the acetylation at the 8th lysine residue of the histone H4 protein. It has been implicated in the prevalence of malaria.

H4K12ac is an epigenetic modification to the DNA packaging protein histone H4. It is a mark that indicates the acetylation at the 12th lysine residue of the histone H4 protein. H4K12ac is involved in learning and memory. It is possible that restoring this modification could reduce age-related decline in memory.

H4K91ac is an epigenetic modification to the DNA packaging protein histone H4. It is a mark that indicates the acetylation at the 91st lysine residue of the histone H4 protein. No known diseases are attributed to this mark but it might be implicated in melanoma.

H3K23ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 23rd lysine residue of the histone H3 protein.

H3K14ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 14th lysine residue of the histone H3 protein.

H3K36ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 36th lysine residue of the histone H3 protein.

H3K56ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 56th lysine residue of the histone H3 protein.

<span class="mw-page-title-main">Mehdi Mollapour</span>

Mehdi Mollapour is a British-American Biochemist and Cancer Biologist. He is a Professor, Vice Chair for Translational Research and Director of Renal Cancer Biology Program for the Department of Urology, and Adjunct Professor at the Department of Biochemistry and Molecular Biology at SUNY Upstate Medical University.

References

  1. 1 2 Nitika; Porter, Corey M.; Truman, Andrew W.; Truttmann, Matthias C. (2020-07-31). "Post-translational modifications of Hsp70 family proteins: Expanding the chaperone code". The Journal of Biological Chemistry. 295 (31): 10689–10708. doi: 10.1074/jbc.REV120.011666 . ISSN   0021-9258. PMC   7397107 . PMID   32518165.
  2. 1 2 3 4 Backe, Sarah J.; Sager, Rebecca A.; Woodford, Mark R.; Makedon, Alan M.; Mollapour, Mehdi (2020-08-07). "Post-translational modifications of Hsp90 and translating the chaperone code". The Journal of Biological Chemistry. 295 (32): 11099–11117. doi: 10.1074/jbc.REV120.011833 . ISSN   0021-9258. PMC   7415980 . PMID   32527727.
  3. ↑ Jakobsson, Magnus E.; Moen, Anders; Bousset, Luc; Egge-Jacobsen, Wolfgang; Kernstock, Stefan; Melki, Ronald; Falnes, Pål Ø. (2013-09-27). "Identification and Characterization of a Novel Human Methyltransferase Modulating Hsp70 Protein Function through Lysine Methylation". The Journal of Biological Chemistry. 288 (39): 27752–27763. doi: 10.1074/jbc.M113.483248 . ISSN   0021-9258. PMC   3784692 . PMID   23921388.
  4. ↑ Kampinga, Harm H.; Craig, Elizabeth A. (August 2010). "The Hsp70 chaperone machinery: J-proteins as drivers of functional specificity". Nature Reviews. Molecular Cell Biology. 11 (8): 579–592. doi:10.1038/nrm2941. ISSN   1471-0072. PMC   3003299 . PMID   20651708.
  5. ↑ Cloutier, Philippe; Coulombe, Benoit (2013). "Regulation of molecular chaperones through post-translational modifications: Decrypting the chaperone code". Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms. 1829 (5): 443–54. doi:10.1016/j.bbagrm.2013.02.010. PMC   4492711 . PMID   23459247.
  6. ↑ Cloutier, Philippe; Lavallée-Adam, Mathieu; Faubert, Denis; Blanchette, Mathieu; Coulombe, Benoit (2013). "A Newly Uncovered Group of Distantly Related Lysine Methyltransferases Preferentially Interact with Molecular Chaperones to Regulate Their Activity". PLOS Genetics. 9 (1): e1003210. doi: 10.1371/journal.pgen.1003210 . PMC   3547847 . PMID   23349634.
  7. ↑ Woodford, Mark R.; Truman, Andrew W.; Dunn, Diana M.; Jensen, Sandra M.; Cotran, Richard; Bullard, Renee; Abouelleil, Mourad; Beebe, Kristin; Wolfgeher, Donald; Wierzbicki, Sara; Post, Dawn E. (2016-02-02). "Mps1 Mediated Phosphorylation of Hsp90 Confers Renal Cell Carcinoma Sensitivity and Selectivity to Hsp90 Inhibitors". Cell Reports. 14 (4): 872–884. doi:10.1016/j.celrep.2015.12.084. ISSN   2211-1247. PMC   4887101 . PMID   26804907.
  8. ↑ Beltrao, Pedro; Albanèse, Véronique; Kenner, Lillian R.; Swaney, Danielle L.; Burlingame, Alma; Villén, Judit; Lim, Wendell A.; Fraser, James S.; Frydman, Judith; Krogan, Nevan J. (2012-07-20). "Systematic Functional Prioritization of Protein Posttranslational Modifications". Cell. 150 (2): 413–425. doi:10.1016/j.cell.2012.05.036. ISSN   0092-8674. PMC   3404735 . PMID   22817900.
  9. ↑ Truman, Andrew; Kristjansdottir, Kolbrun; Wolfgeher, Donald; Hasin, Naushaba; Polier, Sigrun; Zhang, Hong; Perrett, Sarah; Prodromou, Chrisostomos; Jones, Gary; Kron, Stephen (2012-12-07). "CDK-Dependent Hsp70 Phosphorylation Controls G1 Cyclin Abundance and Cell-Cycle Progression". Cell. 151 (6): 1308–1318. doi:10.1016/j.cell.2012.10.051. ISSN   0092-8674. PMC   3778871 . PMID   23217712.
  10. ↑ Mollapour, Mehdi; Tsutsumi, Shinji; Truman, Andrew W.; Xu, Wanping; Vaughan, Cara K.; Beebe, Kristin; Konstantinova, Anna; Vourganti, Srinivas; Panaretou, Barry; Piper, Peter W.; Trepel, Jane B. (2011-03-18). "Threonine 22 phosphorylation attenuates Hsp90 interaction with co-chaperones and affects its chaperone activity". Molecular Cell. 41 (6): 672–681. doi:10.1016/j.molcel.2011.02.011. ISSN   1097-2765. PMC   3062913 . PMID   21419342.
  11. ↑ Lopez, Victor A.; Park, Brenden C.; Nowak, Dominika; Sreelatha, Anju; Zembek, Patrycja; Fernandez, Jessie; Servage, Kelly A.; Gradowski, Marcin; Hennig, Jacek; Tomchick, Diana R.; Pawłowski, Krzysztof (2019-09-19). "A Bacterial Effector Mimics a Host HSP90 Client to Undermine Immunity". Cell. 179 (1): 205–218.e21. doi:10.1016/j.cell.2019.08.020. ISSN   0092-8674. PMC   6754304 . PMID   31522888.
  12. ↑ Donlin, Laura T.; Andresen, Christian; Just, Steffen; Rudensky, Eugene; Pappas, Christopher T.; Kruger, Martina; Jacobs, Erica Y.; Unger, Andreas; Zieseniss, Anke; Dobenecker, Marc-Werner; Voelkel, Tobias (2012-01-15). "Smyd2 controls cytoplasmic lysine methylation of Hsp90 and myofilament organization". Genes & Development. 26 (2): 114–119. doi:10.1101/gad.177758.111. ISSN   0890-9369. PMC   3273835 . PMID   22241783.
  13. ↑ Abu-Farha, Mohamed; Lanouette, Sylvain; Elisma, Fred; Tremblay, Véronique; Butson, Jeffery; Figeys, Daniel; Couture, Jean-François (October 2011). "Proteomic analyses of the SMYD family interactomes identify HSP90 as a novel target for SMYD2". Journal of Molecular Cell Biology. 3 (5): 301–308. doi: 10.1093/jmcb/mjr025 . ISSN   1759-4685. PMID   22028380.
  14. ↑ Rehn, Alexandra; Lawatscheck, Jannis; Jokisch, Marie-Lena; Mader, Sophie L.; Luo, Qi; Tippel, Franziska; Blank, Birgit; Richter, Klaus; Lang, Kathrin; Kaila, Ville R. I.; Buchner, Johannes (May 2020). "A methylated lysine is a switch point for conformational communication in the chaperone Hsp90". Nature Communications. 11 (1): 1219. Bibcode:2020NatCo..11.1219R. doi:10.1038/s41467-020-15048-8. ISSN   2041-1723. PMC   7057950 . PMID   32139682.
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