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  • Review Article
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Reading protein modifications with interaction domains

Nature Reviews Molecular Cell Biology volume 7, pages 473–483 (2006)Cite this article

Key Points

  • Cellular proteins are subject to numerous post-translational modifications (PTMs), which control many aspects of cellular function. Such modifications can regulate protein activity through allosteric effects, but can also create binding sites for a number of modular protein-interaction domains, which recognize, for example, phosphorylated, methylated, acetylated, ubiquitylated or hydroxylated sites. We propose that such PTM-dependent protein?protein interactions represent a fundamental mechanism through which the state of the proteome is interpreted.

  • Although the selective recognition of modified sites by interaction domains is, in principle, rather simple, such interactions can be used to yield more complex responses. For example, they can mediate cooperative or switch-like effects, intramolecular autoregulation, or function in mutually exclusive or antagonistic modes. Furthermore, they often function sequentially to create extended signalling pathways or networks.

  • Protein phosphorylation on Tyr or Ser/Thr residues creates binding sites for a range of interaction domains that provide many examples of the strategies noted above. Strikingly, there are numerous distinct domains that have converged on the common recognition of phosphorylated sites. Phosphorylation-dependent binding to interaction domains functions as a mechanism to couple the multi-site phosphorylation of a single protein to various downstream effectors and regulators, and it can also mediate the effects of multiple different types of PTM. For example, activated receptor tyrosine kinases recruit proteins with multiple phosphotyrosine-recognition domains (such as Src-homology-2 (SH2) and phosphotyrosine-binding (PTB) domains), as well as ubiquitin-binding domains (such as ubiquitin-interacting motifs (UIMs)), to activate signalling pathways and control receptor internalization.

  • PTM-dependent interactions have similar consequences in histone biology. In this case, the predominant modifications involve the acetylation or methylation of Lys residues, which primarily recruit proteins that contain bromodomains or chromodomains. These interactions can be modified by distinct PTMs, such as phosphorylation or sumoylation, and provide a versatile mechanism for the control of chromatin organization and gene expression.

  • The ubiquitylation of proteins creates binding sites for a large number of ubiquitin-binding domains. These can control a wide range of cellular activities, including regulated protein degradation, receptor internalization, the activation of specific signalling pathways and translesion DNA synthesis. We propose that the interactions that are regulated by ubiquitylation follow similar rules to those that apply to phosphorylation-, acetylation- and methylation-dependent interactions.

Abstract

Proteins are controlled by a vast and dynamic array of post-translational modifications, many of which create binding sites for specific protein-interaction domains. We propose that these domains, working together, read the state of the proteome and therefore couple post-translational modifications to cellular organization. We also identify common strategies through which modification-dependent interactions synergize to regulate cell behaviour.

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Figure 1: Example post-translational modification reactions and structures of protein-interaction-domain?ligand complexes.
Figure 2: Examples of the regulatory properties of post-translational modifications and their interaction domains.
Figure 3: Networks of modification-dependent interactions regulate cellular processes.
Figure 4: The combinatorial use of post-translational modifications.
Figure 5: Comparison of the related folds of ubiquitin and SUMO.

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References

  1. Yang, X. J. Multisite protein modification and intramolecular signaling. Oncogene 24, 1653?1662 (2005). An excellent review that describes various ways in which multi-site post-translational modifications can be used to coordinate protein function in a cell.

    Article  CAS  Google Scholar 

  2. Cullen, P. J., Cozier, G. E., Banting, G. & Mellor, H. Modular phosphoinositide-binding domains ? their role in signalling and membrane trafficking. Curr. Biol. 11, R882?R893 (2001).

    Article  CAS  Google Scholar 

  3. Venter, J. C. The sequence of the human genome. Science 291, 1304?1351 (2001).

    Article  CAS  Google Scholar 

  4. Kuriyan, J. & Cowburn, D. Modular peptide recognition domains in eukaryotic signaling. Annu. Rev. Biophys. Biomol. Struct. 26, 259?288 (1997).

    Article  CAS  Google Scholar 

  5. Gimona, M. Protein linguistics ? a grammar for modular protein assembly? Nature Rev. Mol. Cell Biol. 7, 68?73 (2006).

    Article  CAS  Google Scholar 

  6. Waksman, G., Shoelson, S., Pant, N., Cowburn, D. & Kuriyan, J. Binding of a high affinity phosphotyrosyl peptide in the Src SH2 domain: crystal structures of the complexed and peptide-free forms. Cell 72, 779?790 (1993). A seminal structural study that describes the modular nature of the Src SH2 domain and its interaction with a pTyr-containing peptide.

    Article  CAS  Google Scholar 

  7. Owen, D. J. et al. The structural basis for the recognition of acetylated histone H4 by the bromodomain of histone acetyltransferase Gcn5p. EMBO J. 19, 6141?6149 (2000).

    Article  CAS  Google Scholar 

  8. Nielsen, P. R. et al. Structure of the HP1 chromodomain bound to histone H3 methylated at lysine 9. Nature 416, 103?107 (2002).

    Article  CAS  Google Scholar 

  9. Durocher, D. et al. The molecular basis of FHA domain:phosphopeptide binding specificity and implications for phospho-dependent signaling mechanisms. Mol. Cell 6, 1169?1182 (2000).

    Article  CAS  Google Scholar 

  10. Hatada, M. H. et al. Molecular basis for interaction of the protein tyrosine kinase ZAP-70 with the T-cell receptor. Nature 377, 32?38 (1995).

    Article  CAS  Google Scholar 

  11. Hu, J., Liu, J., Ghirlando, R., Saltiel, A. R. & Hubbard, S. R. Structural basis for recruitment of the adaptor protein APS to the activated insulin receptor. Mol. Cell 12, 1379?1389 (2003). Describes a crystal structure that provides an example of how multiple molecular interactions, including the homodimerization of the interaction domain, can cooperatively enhance recruitment to a substrate.

    Article  CAS  Google Scholar 

  12. Nash, P. et al. Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication. Nature 414, 516?523 (2001).

    Article  Google Scholar 

  13. Orlicky, S., Tang, X., Willems, A., Tyers, M. & Sicheri, F. Structural basis for phosphodependent substrate selection and orientation by the SCFCdc4 ubiquitin ligase. Cell 112, 243?256 (2003). References 12 and 13 provide insights into how a threshold number of multiple weak phosphorylation sites on Sic1 cooperate to result in a high-affinity interaction with Cdc4.

    Article  CAS  Google Scholar 

  14. Clapperton, J. A. et al. Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer. Nature Struct. Mol. Biol. 11, 512?518 (2004).

    Article  CAS  Google Scholar 

  15. Haglund, K. & Dikic, I. Ubiquitylation and cell signaling. EMBO J. 24, 3353?3359 (2005).

    Article  CAS  Google Scholar 

  16. Ye, X. et al. Recognition of phosphodegron motifs in human cyclin E by the SCFFbw7 ubiquitin ligase. J. Biol. Chem. 279, 50110?50119 (2004).

    Article  CAS  Google Scholar 

  17. Strohmaier, H. et al. Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line. Nature 413, 268?279 (2001).

    Article  Google Scholar 

  18. Welcker, M. et al. Multisite phosphorylaton by Cdk2 and GSK3 controls cyclin E degradation. Mol. Cell 12, 381?392 (2003).

    Article  CAS  Google Scholar 

  19. Rajagopalan, H. et al. Inactivation of hCDC4 can cause chromosomal instability. Nature 428, 77?81 (2004).

    Article  CAS  Google Scholar 

  20. Pawson, T. & Nash, P. Assembly of cell regulatory systems through protein interaction domains. Science 300, 445?452 (2003).

    Article  CAS  Google Scholar 

  21. Jordan, M. S., Singer, A. L. & Koretzky, G. A. Adaptors as central mediators of signal transduction in immune cells. Nature Immunol. 4, 110?116 (2003).

    Article  CAS  Google Scholar 

  22. Fischle, W. et al. Regulation of HP1?chromatin binding by histone H3 methylation and phosphorylation. Nature 438, 1090?1091 (2005).

    Article  Google Scholar 

  23. Hirota, T., Lipp, J. J., Toh, B. H. & Peters, J. M. Histone H3 serine 10 phosphorylation by Aurora B causes HP1 dissociation from heterochromatin. Nature 438, 1176?1180 (2005). References 22 and 23 provide an example of how PTMs can be used to antagonize interactions with regulatory proteins in order to control gene expression.

    Article  CAS  Google Scholar 

  24. Sicheri, F., Moarefi, I. & Kuriyan, J. Crystal structure of the Src family tyrosine kinase Hck. Nature 385, 602?609 (1997). This paper reveals how the SH2 and SH3 domains of the Src family tyrosine kinase Hck intramolecularly interact with modified peptide motifs in Hck to regulate the kinase activity of the protein.

    Article  CAS  Google Scholar 

  25. Yaffe, M. B. & Elia, A. E. Phosphoserine/threonine-binding domains. Curr. Opin. Cell Biol. 13, 131?138 (2001).

    Article  CAS  Google Scholar 

  26. Bradshaw, J. M. & Waksman, G. Molecular recognition by SH2 domains. Adv. Protein Chem. 61, 161?210 (2002).

    Article  Google Scholar 

  27. Heldin, C. -H., Ostman, A. & Ronnstrand, L. Signal transduction via platelet-derived growth factor receptors. Biochem. Biophys. Acta 1378, F79?F113 (1998).

    CAS  PubMed  Google Scholar 

  28. Hunter, T. Signaling ? 2000 and beyond. Cell 100, 113?127 (2000).

    Article  CAS  Google Scholar 

  29. Schulze, W. X., Deng, L. & Mann, M. Phosphotyrosine interactome of the ErbB-receptor kinase family. Mol. Syst. Biol. 1038, E1?E13 (2005).

    Article  Google Scholar 

  30. Kavanaugh, W. M., Turck, C. W. & Williams, L. T. PTB domain binding to signaling proteins through a sequence motif containing phosphotyrosine. Science 268, 1177?1179 (1995).

    Article  CAS  Google Scholar 

  31. Benes, C. H. et al. The C2 domain of PKCδ is a phosphotyrosine binding domain. Cell 121, 158?160 (2005).

    Article  Google Scholar 

  32. Sun, X. J. et al. Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature 352, 73?77 (1991).

    Article  CAS  Google Scholar 

  33. Uhlik, M. T. et al. Structural and evolutionary division of phosphotyrosine binding (PTB) domains. J. Mol. Biol. 345, 1?20 (2005).

    Article  CAS  Google Scholar 

  34. Yaffe, M. B. et al. The structural basis for 14-3-3:phosphopeptide binding specificity. Cell 91, 961?971 (1997).

    Article  CAS  Google Scholar 

  35. MacKintosh, C. Dynamic interactions between 14-3-3 proteins and phosphoproteins regulate diverse cellular processes. Biochem. J. 381, 329?342 (2004).

    Article  CAS  Google Scholar 

  36. Wu, J. W. et al. Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-signaling. Mol. Cell 8, 1277?1289 (2001).

    Article  CAS  Google Scholar 

  37. Meinhart, A., Kamenski, T., Hoeppner, S., Baumli, S. & Cramer, P. A structural perspective of CTD function. Genes Dev. 19, 1401?1415 (2005).

    Article  CAS  Google Scholar 

  38. Fabrega, C., Shen, V., Shuman, S. & Lima, C. D. Structure of an mRNA capping enzyme bound to the phosphorylated carboxy-terminal domain of RNA polymerase II. Mol. Cell 11, 1549?1561 (2003).

    Article  CAS  Google Scholar 

  39. Li, M. et al. Solution structure of the Set2?Rpb1 interacting domain of human Set2 and its interaction with the hyperphosphorylated C-terminal domain of Rpb1. Proc. Natl Acad. Sci. USA 102, 17636?17641 (2005).

    Article  CAS  Google Scholar 

  40. Keogh, M. C. et al. Cotranscriptional Set2 methylation of histone H3 lysine 36 recruits a repressive Rpd3 complex. Cell 123, 593?605 (2005).

    Article  CAS  Google Scholar 

  41. Jenuwein, T. & Allis, C. D. Translating the histone code. Science 203, 1074?1080 (2001).

    Article  Google Scholar 

  42. Jacobs, S. A. & Khorasanizadeh, S. Structure of HP1 chromodomain bound to a lysine 9-methylated histone H3 tail. Science 295, 2080?2083 (2002).

    Article  CAS  Google Scholar 

  43. Jacobson, R. H., Ladurner, A. G., King, D. S. & Tjian, R. Structure and function of a human TAFII250 double bromodomain module. Science 288, 1422?1425 (2000).

    Article  CAS  Google Scholar 

  44. Flanagan, J. F. et al. Double chromodomains cooperate to recognize the methylated histone H3 tail. Nature 438, 1090?1091 (2005). References 43 and 44 illustrate the use of tandem interaction domains to recognize two adjacent modified peptide motifs.

    Article  Google Scholar 

  45. Kim, J. et al. Tudor, MBT and chromo domains gauge the degree of lysine methylation. EMBO Rep. 7, 397?403 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Wysocka, J. et al. WDR5 associates with histone H3 methylated at K4 and is essential for H3 K4 methylation and vertebrate development. Cell 121, 859?872 (2005).

    Article  CAS  Google Scholar 

  47. Han, Z. et al. Structural basis for the specific recognition of methylated histone H3 lysine 4 by the WD-40 protein WDR5. Mol. Cell 22, 137?144 (2006).

    Article  CAS  Google Scholar 

  48. Huang, Y., Fang, J., Bedford, M. T., Zhang, Y. & Xu, R. M. Recognition of histone H3 lysine-4 methylation by the double tudor domain of JMJD2A. Science 312, 748?751 (2006).

    Article  CAS  Google Scholar 

  49. Macdonald, N. et al. Molecular basis for the recognition of phosphorylated and phosphoacetylated histone H3 by 14-3-3. Mol. Cell 20, 199?211 (2005).

    Article  CAS  Google Scholar 

  50. Stucki, M. et al. MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks. Cell 123, 1213?1226 (2005).

    Article  CAS  Google Scholar 

  51. Yan, K. S. & Zhou, M. -M. in Modular Protein Domains Ch. 11 (eds Cesarini, G., Gimona, M., Sudol, M. & Yaffe, M.) 227?236 (Wiley-VCH, Weinheim, 2005).

    Book  Google Scholar 

  52. Pickart, C. M. Mechanisms underlying ubiquitination. Annu. Rev. Biochem. 70, 503?533 (2001).

    Article  CAS  Google Scholar 

  53. Pickart, C. M. & Eddins, M. J. Ubiquitin: structures, functions, mechanisms. Biochim. Biophys. Acta 1695, 55?72 (2004).

    Article  CAS  Google Scholar 

  54. Haglund, K., Di Fiore, P. P. & Dikic, I. Distinct monoubiquitin signals in receptor endocytosis. Trends Biochem. 28, 598?603 (2003).

    Article  CAS  Google Scholar 

  55. Pickart, C. M. & Fushman, D. Polyubiquitin chains: polymeric protein signals. Curr. Opin. Chem. Biol. 8, 610?616 (2004).

    Article  CAS  Google Scholar 

  56. Hicke, L., Schubert, H. L. & Hill, C. P. Ubiquitin-binding domains. Nature Rev. Mol. Cell Biol. 6, 610?621 (2005).

    Article  CAS  Google Scholar 

  57. Penengo, L. et al. Crystal structure of the ubiquitin binding domains of Rabex-5 reveals two modes of interaction with ubiquitin. Cell 124, 1183?1195 (2006).

    Article  CAS  Google Scholar 

  58. Lee, S. et al. Structural basis for ubiquitin recognition and autoubiquitination by Rabex-5. Nature Struct. Mol. Biol. 13, 186?188 (2006).

    Article  Google Scholar 

  59. Bienko, M. et al. Ubiquitin-binding domains in Y-family polymerases regulate translesion synthesis. Science 310, 1821?1824 (2005). This paper reveals novel ubiquitin interactions and their role in the repair of DNA lesions.

    Article  CAS  Google Scholar 

  60. Varadan, R., Assfalg, M., Raasi, S., Pickart, C. & Fushman, D. Structural determinants for selective recognition of a Lys48-linked polyubiquitin chain by a UBA domain. Mol. Cell 18, 687?698 (2005).

    Article  CAS  Google Scholar 

  61. Krappmann, D. & Scheidereit, C. A pervasive role of ubiquitin conjugation in activation and termination of IκB kinase pathways. EMBO Rep. 6, 321?326 (2005).

    Article  CAS  Google Scholar 

  62. Stelter, P. & Ulrich, H. D. Control of spontaneous and damage-induced mutagenesis by SUMO and ubiquitin conjugation. Nature 425, 188?191 (2003).

    Article  CAS  Google Scholar 

  63. Song, J., Durrin, L. K., Wilkinson, T. A., Krontiris, T. G. & Chen, Y. Identification of a SUMO-binding motif that recognizes SUMO-modified proteins. Proc. Natl Acad. Sci. USA 101, 14373?14378 (2004).

    Article  CAS  Google Scholar 

  64. Hecker, C. M., Rabiller, M., Haglund, K., Bayer, P. & Dikic, I. Specification of SUMO1- and SUMO2-interacting motifs. J. Biol. Chem. 281, 16117?16127 (2006).

    Article  CAS  Google Scholar 

  65. Pfander, B., Moldovan, G. L., Sacher, M., Hoege, C. & Jentsch, S. SUMO-modified PCNA recruits Srs2 to prevent recombination during S phase. Nature 436, 428?433 (2005).

    Article  CAS  Google Scholar 

  66. Papouli, E. et al. Crosstalk between SUMO and ubiquitin on PCNA is mediated by recruitment of the helicase Srs2p. Mol. Cell 19, 123?133 (2005).

    Article  CAS  Google Scholar 

  67. Shalizi, A. et al. A calcium-regulated MEF2 sumoylation switch controls postsynaptic differentiation. Science 311, 1012?1017 (2006).

    Article  CAS  Google Scholar 

  68. Polo, S. et al. A single motif responsible for ubiquitin recognition and monoubiquitination in endocytic proteins. Nature 416, 451?455 (2002).

    Article  CAS  Google Scholar 

  69. Hoeller, D. et al. Regulation of ubiquitin-binding proteins by monoubiquitination. Nature Cell Biol. 8, 163?169 (2006).

    Article  CAS  Google Scholar 

  70. Piccione, E. et al. Phosphatidylinositol 3-kinase p85 SH2 domain specificity defined by direct phosphopeptide/SH2 domain binding. Biochem. 32, 3197?3202 (1993).

    Article  CAS  Google Scholar 

  71. Jones, R. B., Gordus, A., Krall, J. A. & Macbeath, G. A quantitative protein interaction network for the ErbB receptors using protein microarrays. Nature 439, 168?174 (2006).

    Article  CAS  Google Scholar 

  72. Hanson, S. M. et al. Differential interaction of spin-labeled arrestin with inactive and active phosphorhodopsin. Proc. Natl Acad. Sci. USA 103, 4900?4905 (2006).

    Article  CAS  Google Scholar 

  73. Huber, A. H. & Weis, W. L. The structure of the β-catenin/E-cadherin complex and the molecular basis of diverse ligand recognition by β-catenin. Cell 105, 391?402 (2001).

    Article  CAS  Google Scholar 

  74. Song, J., Zhang, Z., Hu, W. & Chen, Y. Small ubiquitin-like modifier (SUMO) recognition of a SUMO binding motif: a reversal of the bound orientation. J. Biol. Chem. 280, 40122?40129 (2005).

    Article  CAS  Google Scholar 

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Acknowledgements

We are indebted to C. Lim and M. Rabiller for assistance with the figures, and to R. Linding and M. Tyers for insightful comments. B.T.S. is funded by a fellowship from the Cancer Research Institute (New York, USA). Work in the authors' laboratories is funded by the Canadian Institutes for Health Research (CIHR) and the National Cancer Institute of Canada and Genome Canada (T.P.), the Deutsche Forschungsgemeinschaft and the German?Israeli Foundation (I.D.), and the United States National Institutes of Health (M.-M.Z). T.P. is a distinguished investigator of the CIHR.

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Authors and Affiliations

  1. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, M5G 1X5, Ontario, Canada

    Bruce T. Seet & Tony Pawson

  2. Institute of Biochemistry II, Goethe University School of Medicine, University Hospital, Building 75, Theodour-Stern-Kai 7, Frankfurt, D-60590, Germany

    Ivan Dikic

  3. Department of Molecular Physiology and Biophysics, Mount Sinai School of Medicine, New York University, One Gustave L. Levy Place, New York, 10029, New York, USA

    Ming-Ming Zhou

  4. Department of Medical Genetics and Microbiology, University of Toronto, Toronto, M5S 1A8, Ontario, Canada

    Tony Pawson

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  1. Bruce T. Seet
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Correspondence to Tony Pawson.

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DATABASES

Protein Data Bank

1E6I

1JYR

1LM8

1Q0W

1Q3L

2ASQ

FURTHER INFORMATION

The Pawson Lab

POSTER

Reading protein and phospholipid modifications with interaction domains

Glossary

Phosphoinositide

A phosphorylated derivative of the glycerolipid phosphatidylinositol.

Allosteric regulation

The regulation of a protein's activity through a conformational change that is induced by the binding of a ligand or the addition of a post-translational modification at a region other than the substrate-binding site.

Src-homology-2 (SH2) domain

A 100-residue domain that binds to particular phosphorylated Tyr sequences in proteins.

Pleckstrin-homology domain

(PH domain). The PH domain is ∼120 amino acids. It typically interacts with various phosphoinositides, and is thereby involved in targeting proteins to membranes.

WD40-repeat domain

A repeat sequence of 40?60 amino acids that usually ends with Trp and Asp (WD). Consecutive repeats fold into a circular β-propeller structure.

E3 ubiquitin ligase

An enzyme that functions with a ubiquitin-conjugating enzyme (E2) to link one or more ubiquitin molecules to a target protein, which marks the protein for subsequent recognition by ubiquitin-binding domains. SCF-type ubiquitin ligases are one of the principal classes of E3 ligase. They are complexes that consist of SKP1, cullin and F-box proteins.

Proteasome

A large multiprotein complex that is responsible for degrading intracellular proteins that have been tagged for destruction by the addition of ubiquitin.

Breast-cancer-susceptibility protein-1 C-terminal domain

(BRCT domain). The BRCT domain is 90?100 amino acids and occurs either as a single element or as multiple repeats. It binds to phosphopeptides in several proteins that are involved in DNA-damage response and DNA repair.

Ubiquitin-binding domains

The collective term that is given to modular interaction domains that bind to ubiquitin.

Scaffold

A protein that supports the assembly of a multiprotein complex through interactions with other proteins.

Chromodomain

A protein domain that often binds to methylated Lys residues in target proteins.

14-3-3 proteins

A family of proteins that bind to phosphorylated Ser/Thr residues in a context-specific manner.

Src-family kinases

Kinases that belong to the Src family of tyrosine kinases, which is the largest of the non-receptor-tyrosine-kinase families. Members include Src, Yes, Fyn, Lck, Lyn, Blk, Hck, Fgr and Yrk.

Src-homology-3 (SH3) domain

A protein sequence of ∼50 amino acids that binds to Pro-rich regions of proteins. Some SH3 domains have been identified that bind to atypical non-Pro-based motifs.

Phosphotyrosine-binding domain

(PTB domain). A domain of 100?150 amino acids. Some PTB domains bind to specific phosphotyrosine sites, which usually have the consensus sequence Asn-Pro-X-pTyr (NPXpY).

Conserved region-2 of protein kinase C domain

(C2 domain). A domain that was originally found to bind to lipids in a Ca2+-dependent manner. However, an exception has been identified in the C2 domain of protein kinase Cδ, which binds to specific phosphotyrosine-containing peptides.

WW domain

A protein domain of ∼35 amino acids that binds to Pro-rich peptide motifs or, in some cases, to pSer/pThr-Pro motifs.

FF domain

A protein domain of 50?60 amino acids. FF domains are always arranged in tandem repeats and bind to acidic or phosphorylated peptide motifs.

SRI domain

(Set2 Rpb1 interacting domain). An ∼100-amino-acid domain that is conserved among a number of putative Set2 homologues. The SRI domain of Set2 binds to the phosphorylated C-terminal domain of RNA polymerase II.

C-terminal-interaction domains

(CIDs). CIDs are domains that bind to phosphorylated heptad repeats in the C-terminal domain of RNA polymerase II.

Histone deacetylase

An enzyme that removes acetyl groups from Lys residues of a histone protein. Histone acetyltransferases function in the opposite manner to add acetyl groups to Lys residues of a histone protein.

Bromodomain

An evolutionarily conserved protein domain that often binds to acetylated Lys residues in target proteins.

Epigenetic

Heritable information that is encoded by modifications of the genome and chromatin components, which affect gene expression without changing the nucleotide sequence.

TUDOR domain

A conserved chromodomain-like protein domain. Some TUDOR domains bind to methylated Lys or Arg residues.

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Seet, B., Dikic, I., Zhou, MM. et al. Reading protein modifications with interaction domains. Nat Rev Mol Cell Biol 7, 473–483 (2006). https://doi.org/10.1038/nrm1960

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