Structural basis of docking interactions between ERK2 and MAP kinase phosphatase 3
Abstract
Mitogen-activated protein (MAP) kinases are central components of signal transduction pathways for cell proliferation, stress responses, and differentiation. Signaling efficiency and specificity are modulated in large part by docking interactions between individual MAP kinase and the kinase interaction motif (KIM), (R/K) 2–3 -X 1–6 -Φ A -X-Φ B , in its cognate kinases, phosphatases, scaffolding proteins, and substrates. We have determined the crystal structure of extracellular signal-regulated protein kinase 2 bound to the KIM peptide from MAP kinase phosphatase 3, an extracellular signal-regulated protein kinase 2-specific phosphatase. The structure reveals that the KIM docking site, situated in a noncatalytic region opposite of the kinase catalytic pocket, is comprised of a highly acidic patch and a hydrophobic groove, which engage the basic and Φ A -X-Φ B residues, respectively, in the KIM sequence. The specific docking interactions observed in the structure consolidate all known biochemical data. In addition, structural comparison indicates that the KIM docking site is conserved in all MAP kinases. The results establish a structural model for understanding how MAP kinases interact with their regulators and substrates and provide new insights into how MAP kinase docking specificity can be achieved.
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MAPK docking is a well-characterized protein-peptide interaction system.
“At the structural level, MAPK docking is a well characterized protein-peptide interaction system (9, 12-16).”
From Specificity of Linear Motifs That Bind to a Common Mitogen-Activated Protein Kinase Docking Groove (2012) · cites this paper as [14]
Cites
Crystallography & NMR System: A New Software Suite for Macromolecular Structure Determination
Brünger, A. T., Adams, P. D., Clore, G. M., DeLano, W. L., Gros, P., Grosse‐Kunstleve, R. W., Jiang, J., Kuszewski, J. J., Nilges, M., Pannu, N., et al. (1998) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444998003254 · Cited by 15,720 · see citing works
Jones, T. A., Zou, J.-Y., Cowan, S. W., & Kjeldgaard, M. (1991) · Acta Crystallographica Section A Foundations of Crystallography · doi:10.1107/s0108767390010224 · Cited by 12,650 · see citing works
Mitogen-Activated Protein Kinase: Conservation of a Three-Kinase Module From Yeast to Human
Widmann, C., Gibson, S. B., Jarpe, M. B., & Johnson, G. L. (1999) · Physiological Reviews · doi:10.1152/physrev.1999.79.1.143 · Cited by 2,707 · see citing works
A conserved docking motif in MAP kinases common to substrates, activators and regulators
Tanoue, T., Adachi, M., Moriguchi, T., & Nishida, E. (2000) · Nature Cell Biology · doi:10.1038/35000065 · Cited by 816 · see citing works
Dual specificity phosphatases: a gene family for control of MAP kinase function
Camps, M., NICHOLS, A., & Arkinstall, S. (2000) · The FASEB Journal · doi:10.1096/fasebj.14.1.6 · Cited by 812 · see citing works
Protein phosphatases and the regulation of mitogen-activated protein kinase signalling
Keyse, S. M. (2000) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(99)00075-7 · Cited by 808 · see citing works
Chen, Z., Gibson, T. B., Robinson, F. L., Silvestro, L., Pearson, G. W., Xu, B.-E., Wright, A., Vanderbilt, C. A., & Cobb, M. H. (2001) · Chemical Reviews · doi:10.1021/cr000241p · Cited by 789 · see citing works
Activation mechanism of the MAP kinase ERK2 by dual phosphorylation
Canagarajah, B. J., Khokhlatchev, A., Cobb, M. H., & Goldsmith, E. J. (1997) · Cell · doi:10.1016/s0092-8674(00)80351-7 · Cited by 729 · see citing works
Implementation of molecular replacement in AMoRe
Navaza, J. (2001) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444901012422 · Cited by 615 · see citing works
Atomic structure of the MAP kinase ERK2 at 2.3 A resolution
Zhang, F., Strand, A., Robbins, D., Cobb, M. H., & Goldsmith, E. J. (1994) · Nature · doi:10.1038/367704a0 · Cited by 592 · see citing works
The JIP Group of Mitogen-Activated Protein Kinase Scaffold Proteins
Yasuda, J., Whitmarsh, A. J., Cavanagh, J., Sharma, M., & Davis, R. J. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.10.7245 · Cited by 458 · see citing works
Chu, Y., Solski, P. A., Khosravi‐Far, R., Der, C. J., & Kelly, K. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.11.6497 · Cited by 442 · see citing works
Docking domains and substrate-specificity determination for MAP kinases
Sharrocks, A. D., Yang, S.-H., & Galanis, A. (2000) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(00)01627-3 · Cited by 442 · see citing works
Brunner, D., Oellers, N., Szabad, J., Biggs, W., Zipursky, S. L., & Hafen, E. (1994) · Cell · doi:10.1016/0092-8674(94)90362-x · Cited by 409 · see citing works
Pulido, R., Zúñiga, Á., & Ullrich, A. (1998) · The EMBO Journal · doi:10.1093/emboj/17.24.7337 · Cited by 320 · see citing works
Chang, C.-I., Xu, B.-E., Akella, R., Cobb, M. H., & Goldsmith, E. J. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00525-7 · Cited by 302 · see citing works
Tanoue, T., Maeda, R., Adachi, M., & Nishida, E. (2001) · The EMBO Journal · doi:10.1093/emboj/20.3.466 · Cited by 285 · see citing works
Smith, J. A., Poteet-Smith, C. E., Malarkey, K., & Sturgill, T. W. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.5.2893 · Cited by 283 · see citing works
Structural basis for the selective inhibition of JNK1 by the scaffolding protein JIP1 and SP600125
Heo, Y., Kim, S., Seo, C. I., Kim, Y. K., Sung, B., Lee, H. S., Lee, J. I., Park, S., Kim, J. H., Hwang, K. Y., et al. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600212 · Cited by 275 · see citing works
The Specificity of Extracellular Signal-regulated Kinase 2 Dephosphorylation by Protein Phosphatases
Zhou, B., Wang, Z.-X., Zhao, Y. C., Brautigan, D. L., & Zhang, Z. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m203969200 · Cited by 211 · see citing works
Self-citationZhao, Y., & Zhang, Z. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m103369200 · Cited by 175 · see citing works
Self-citationA MAP kinase docking site is required for phosphorylation and activation of p90rsk/MAPKAP kinase-1
Gavin, A.-C., & Nebreda, A. R. (1999) · Current Biology · doi:10.1016/s0960-9822(99)80120-1 · Cited by 158 · see citing works
Saxena, M., Williams, S., Brockdorff, J. L., Gilman, J., & Mustelin, T. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.17.11693 · Cited by 135 · see citing works
Protein modification: Docking sites for kinases
Holland, P. M., & Cooper, J. A. (1999) · Current Biology · doi:10.1016/s0960-9822(99)80205-x · Cited by 125 · see citing works
Identification of Novel Extracellular Signal-Regulated Kinase Docking Domain Inhibitors
Hancock, C. N., Macias, A. T., Lee, E. K., Yu, S. Y., MacKerell, A. D., & Shapiro, P. S. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm0501174 · Cited by 117 · see citing works
Multiple Regions of MAP Kinase Phosphatase 3 Are Involved in Its Recognition and Activation by ERK2
Zhou, B., Wu, L., Shen, K., Zhang, J., Lawrence, D. S., & Zhang, Z. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m009753200 · Cited by 116 · see citing works
Self-citationData collection and processing
Turkenburg, J. P., & Brady, L. (1999) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444999013761 · Cited by 115 · see citing works
Bott, C. M., Thorneycroft, S. G., & Marshall, C. (1994) · FEBS Letters · doi:10.1016/0014-5793(94)00958-9 · Cited by 105 · see citing works
BARDWELL, A. J., ABDOLLAHI, M., & BARDWELL, L. (2003) · Biochemical Journal · doi:10.1042/bj20021806 · Cited by 97 · see citing works
Nichols, A. C., Camps, M., Gilliéron, C., Chabert, C., Brunet, A., Wilsbacher, J. L., Cobb, M. H., Pouysségur, J., Shaw, J. P., & Arkinstall, S. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m001515200 · Cited by 95 · see citing works
A Bipartite Mechanism for ERK2 Recognition by Its Cognate Regulators and Substrates
Zhang, J., Zhou, B., Zheng, C.-F., & Zhang, Z. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m303909200 · Cited by 92 · see citing works
Self-citationModular Structure of a Docking Surface on MAPK Phosphatases
Tanoue, T., Yamamoto, T., & Nishida, E. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m202096200 · Cited by 78 · see citing works
Karim, F. D., & Rubin, G. M. (1999) · Molecular Cell · doi:10.1016/s1097-2765(01)80006-x · Cited by 71 · see citing works
Mechanism of Mitogen-activated Protein Kinase Phosphatase-3 Activation by ERK2
Zhou, B., & Zhang, Z. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.50.35526 · Cited by 69 · see citing works
Self-citationGenetic Analysis of rolled, Which Encodes a Drosophila Mitogen-Activated Protein Kinase
Lim, Y., Nishizawa, K., Nishi, Y., Tsuda, L., Inoue, Y. H., & Nishida, Y. (1999) · Genetics · doi:10.1093/genetics/153.2.763 · Cited by 27 · see citing works
Molecular Determinants of Substrate Recognition in Hematopoietic Protein-tyrosine Phosphatase
Huang, Z., Zhou, B., & Zhang, Z.-Y. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m407820200 · Cited by 23 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases
Owens, D. M., & Keyse, S. M. (2007) · Oncogene · doi:10.1038/sj.onc.1210412 · Cited by 777 · see citing works
Dual‐specificity MAP kinase phosphatases (MKPs): Shaping the outcome of MAP kinase signalling
Caunt, C. J., & Keyse, S. M. (2013) · The FEBS Journal · doi:10.1111/j.1742-4658.2012.08716.x · Cited by 535 · see citing works
Molecular basis of MAP kinase regulation
Peti, W., & Page, R. (2013) · Protein Science · doi:10.1002/pro.2374 · Cited by 302 · see citing works
Docking interactions in protein kinase and phosphatase networks
Reményi, A., Good, M. C., & Lim, W. A. (2006) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2006.10.008 · Cited by 188 · see citing works
Specificity of Linear Motifs That Bind to a Common Mitogen-Activated Protein Kinase Docking Groove
Garai, Á., Zeke, A., Gógl, G., Törő, I., Fördős, F., Blankenburg, H., Bárkai, T., Varga, J., Alexa, A., Emig, D., et al. (2012) · Science Signaling · doi:10.1126/scisignal.2003004 · Cited by 177 · see citing works
Substrate and Docking Interactions in Serine/Threonine Protein Kinases
Goldsmith, E. J., Akella, R., Min, X., Zhou, T., & Humphreys, J. M. (2007) · Chemical Reviews · doi:10.1021/cr068221w · Cited by 143 · see citing works
Selectivity of Docking Sites in MAPK Kinases
Bardwell, A. J., Frankson, E., & Bardwell, L. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m900080200 · Cited by 127 · see citing works
Unique MAP Kinase binding sites
Akella, R., Moon, T. M., & Goldsmith, E. J. (2008) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2007.09.016 · Cited by 108 · see citing works
Structure of ERK2 bound to PEA-15 reveals a mechanism for rapid release of activated MAPK
Mace, P. D., Wallez, Y., Egger, M. F., Dobaczewska, M. K., Robinson, H., Pasquale, E. B., & Riedl, S. J. (2013) · Nature Communications · doi:10.1038/ncomms2687 · Cited by 97 · see citing works
Structural basis of p38α regulation by hematopoietic tyrosine phosphatase
Francis, D. M., Różycki, B., Koveal, D., Hummer, G., Page, R., & Peti, W. (2011) · Nature Chemical Biology · doi:10.1038/nchembio.707 · Cited by 79 · see citing works
Zhang, Y.-Y., Wu, J.-W., & Wang, Z.-X. (2011) · Science Signaling · doi:10.1126/scisignal.2002241 · Cited by 52 · see citing works
BARDWELL, L., & SHAH, K. (2006) · Methods · doi:10.1016/j.ymeth.2006.06.008 · Cited by 46 · see citing works
Solution NMR Insights into Docking Interactions Involving Inactive ERK2
Piserchio, A., Warthaka, M., Devkota, A. K., Kaoud, T. S., Lee, S., Abramczyk, O., Ren, P., Dalby, K. N., & Ghose, R. (2011) · Biochemistry · doi:10.1021/bi2000559 · Cited by 41 · see citing works
Understanding the specificity of a docking interaction between JNK1 and the scaffolding protein JIP1
Yan, C., Kaoud, T., Lee, S., Dalby, K. N., & Ren, P. (2011) · The Journal of Physical Chemistry B · doi:10.1021/jp1073522 · Cited by 36 · see citing works
Resting and Active States of the ERK2:HePTP Complex
Francis, D. M., Różycki, B., Tortajada, A., Hummer, G., Peti, W., & Page, R. (2011) · Journal of the American Chemical Society · doi:10.1021/ja2075136 · Cited by 32 · see citing works
The Third Conformation of p38α MAP Kinase Observed in Phosphorylated p38α and in Solution
Akella, R., Min, X., Wu, Q., Gardner, K. H., & Goldsmith, E. J. (2010) · Structure · doi:10.1016/j.str.2010.09.015 · Cited by 31 · see citing works
Lee, S., Warthaka, M., Yan, C., Kaoud, T. S., Piserchio, A., Ghose, R., Ren, P., & Dalby, K. N. (2011) · PLoS ONE · doi:10.1371/journal.pone.0018594 · Cited by 26 · see citing works
Kumar, G. S., Zettl, H., Page, R., & Peti, W. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.499178 · Cited by 12 · see citing works
Three-dimensional docking in the MAPK p38α
Goldsmith, E. J. (2011) · Science Signaling · doi:10.1126/scisignal.2002697 · Cited by 8 · see citing works
- Authors
- Liu, S., Sun, J.-P., Zhou, B., & Zhang, Z.-Y.
- Affiliations
- Indiana University School of Medicine (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-04-04
- Volume
- 103
- Issue
- 14
- Pages
- 5326-5331
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2030976054
- Cited by
- 140
- References
- 36
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 4 · 2023: 4 · 2022: 11 · 2021: 4 · 2020: 3 · 2019: 6 · 2018: 5 · 2017: 4 · 2016: 8 · 2015: 5 · 2014: 3 · 2013: 11 · 2012: 14
- FWCI
- 4.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA-69202, R01CA069202)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- ERK2, MAPK signaling, crystal structure, acidic patch, hydrophobic groove, protein-protein interaction
- MeSH terms
- Amino Acid Sequence, Binding Sites, Models, Molecular, Molecular Sequence Data, Protein Binding, Protein Tyrosine Phosphatases, Sequence Homology, Amino Acid, Mitogen-Activated Protein Kinase 1, Amino Acid Motifs, Dual Specificity Phosphatase 6
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