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Autoregulation by the juxtamembrane region of the human ephrin receptor tyrosine kinase A3 (EphA3).

Davis TL, Walker JR, Loppnau P, Butler-Cole C, Allali-Hassani A, Dhe-Paganon S
Structure 16 873-84 (2008)
Related entries: 2qo2, 2qo7, 2qo9, 2qob, 2qoc, 2qod, 2qof, 2qoi, 2qok, 2qol, 2qon, 2qoo

Cited: 48 times
EuropePMC logo PMID: 18547520

Abstract

Ephrin receptors (Eph) affect cell shape and movement, unlike other receptor tyrosine kinases that directly affect proliferative pathways. The kinase domain of EphA3 is activated by ephrin binding and receptor oligomerization. This activation is associated with two tyrosines in the juxtamembrane region; these tyrosines are sites of autophosphorylation and interact with the active site of the kinase to modulate activity. This allosteric event has important implications both in terms of understanding signal transduction pathways mediated by Eph kinases as well as discovering specific therapeutic ligands for receptor kinases. In order to provide further details of the molecular mechanism through which the unphosphorylated juxtamembrane region blocks catalysis, we studied wild-type and site-specific mutants in detail. High-resolution structures of multiple states of EphA3 kinase with and without the juxtamembrane segment allowed us to map the coupled pathway of residues that connect the juxtamembrane segment, the activation loop, and the catalytic residues of the kinase domain. This highly conserved set of residues likely delineates a molecular recognition pathway for most of the Eph RTKs, helping to characterize the dynamic nature of these physiologically important enzymes.

Articles - 2qoq mentioned but not cited (4)

  1. Cancer somatic mutations disrupt functions of the EphA3 receptor tyrosine kinase through multiple mechanisms. Lisabeth EM, Fernandez C, Pasquale EB. Biochemistry 51 1464-1475 (2012)
  2. Structural recognition of an optimized substrate for the ephrin family of receptor tyrosine kinases. Davis TL, Walker JR, Allali-Hassani A, Parker SA, Turk BE, Dhe-Paganon S. FEBS J 276 4395-4404 (2009)
  3. Predicting inactive conformations of protein kinases using active structures: conformational selection of type-II inhibitors. Xu M, Yu L, Wan B, Yu L, Huang Q. PLoS One 6 e22644 (2011)
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  1. Molecular mechanism of Aurora A kinase autophosphorylation and its allosteric activation by TPX2. Zorba A, Buosi V, Kutter S, Kern N, Pontiggia F, Cho YJ, Kern D. Elife 3 e02667 (2014)
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  5. In situ analysis of tyrosine phosphorylation networks by FLIM on cell arrays. Grecco HE, Roda-Navarro P, Girod A, Hou J, Frahm T, Truxius DC, Pepperkok R, Squire A, Bastiaens PI. Nat Methods 7 467-472 (2010)
  6. Protein structural ensembles are revealed by redefining X-ray electron density noise. Lang PT, Holton JM, Fraser JS, Alber T. Proc Natl Acad Sci U S A 111 237-242 (2014)
  7. Effects of cancer-associated EPHA3 mutations on lung cancer. Zhuang G, Song W, Amato K, Hwang Y, Lee K, Boothby M, Ye F, Guo Y, Shyr Y, Lin L, Carbone DP, Brantley-Sieders DM, Chen J. J Natl Cancer Inst 104 1182-1197 (2012)
  8. Ubiquitination switches EphA2 vesicular traffic from a continuous safeguard to a finite signalling mode. Sabet O, Stockert R, Xouri G, Brüggemann Y, Stanoev A, Bastiaens PIH. Nat Commun 6 8047 (2015)
  9. Structural insights into the inhibited states of the Mer receptor tyrosine kinase. Huang X, Finerty P, Walker JR, Butler-Cole C, Vedadi M, Schapira M, Parker SA, Turk BE, Thompson DA, Dhe-Paganon S. J Struct Biol 165 88-96 (2009)
  10. A semisynthetic Eph receptor tyrosine kinase provides insight into ligand-induced kinase activation. Singla N, Erdjument-Bromage H, Himanen JP, Muir TW, Nikolov DB. Chem Biol 18 361-371 (2011)
  11. A role of the SAM domain in EphA2 receptor activation. Shi X, Hapiak V, Zheng J, Muller-Greven J, Bowman D, Lingerak R, Buck M, Wang BC, Smith AW. Sci Rep 7 45084 (2017)
  12. Structures of the EphA2 Receptor at the Membrane: Role of Lipid Interactions. Chavent M, Seiradake E, Jones EY, Sansom MS. Structure 24 337-347 (2016)
  13. Perineuronal Net Protein Neurocan Inhibits NCAM/EphA3 Repellent Signaling in GABAergic Interneurons. Sullivan CS, Gotthard I, Wyatt EV, Bongu S, Mohan V, Weinberg RJ, Maness PF. Sci Rep 8 6143 (2018)
  14. Double-edged sword effect of biochanin to inhibit nuclear factor kappaB: suppression of serine/threonine and tyrosine kinases. Manna SK. Biochem Pharmacol 83 1383-1392 (2012)
  15. Functional analysis of chimeric lysin motif domain receptors mediating Nod factor-induced defense signaling in Arabidopsis thaliana and chitin-induced nodulation signaling in Lotus japonicus. Wang W, Xie ZP, Staehelin C. Plant J 78 56-69 (2014)
  16. A high-content cellular senescence screen identifies candidate tumor suppressors, including EPHA3. Lahtela J, Corson LB, Hemmes A, Brauer MJ, Koopal S, Lee J, Hunsaker TL, Jackson PK, Verschuren EW. Cell Cycle 12 625-634 (2013)
  17. Discovery of tyrosine kinase inhibitors by docking into an inactive kinase conformation generated by molecular dynamics. Zhao H, Huang D, Caflisch A. ChemMedChem 7 1983-1990 (2012)
  18. Completing the structural family portrait of the human EphB tyrosine kinase domains. Overman RC, Debreczeni JE, Truman CM, McAlister MS, Attwood TK. Protein Sci 23 627-638 (2014)
  19. Coupled regulation by the juxtamembrane and sterile α motif (SAM) linker is a hallmark of ephrin tyrosine kinase evolution. Kwon A, John M, Ruan Z, Kannan N. J Biol Chem 293 5102-5116 (2018)
  20. EphA3 functions are regulated by collaborating phosphotyrosine residues. Shi G, Yue G, Zhou R. Cell Res 20 1263-1275 (2010)
  21. The Neural Cell Adhesion Molecule (NCAM) Promotes Clustering and Activation of EphA3 Receptors in GABAergic Interneurons to Induce Ras Homolog Gene Family, Member A (RhoA)/Rho-associated protein kinase (ROCK)-mediated Growth Cone Collapse. Sullivan CS, Kümper M, Temple BS, Maness PF. J Biol Chem 291 26262-26272 (2016)
  22. Distinctive Structure of the EphA3/Ephrin-A5 Complex Reveals a Dual Mode of Eph Receptor Interaction for Ephrin-A5. Forse GJ, Uson ML, Nasertorabi F, Kolatkar A, Lamberto I, Pasquale EB, Kuhn P. PLoS One 10 e0127081 (2015)
  23. EPH-EPHRIN in human gastrointestinal cancers. Sugimura H, Wang JD, Mori H, Tsuboi M, Nagura K, Igarashi H, Tao H, Nakamura R, Natsume H, Kahyo T, Shinmura K, Konno H, Hamaya Y, Kanaoka S, Kataoka H, Zhou XJ. World J Gastrointest Oncol 2 421-428 (2010)
  24. Insights into molecular interactions between the juxtamembrane and kinase subdomains of the Arabidopsis Crinkly-4 receptor-like kinase. Meyer MR, Shah S, Rao AG. Arch Biochem Biophys 535 101-110 (2013)
  25. A new autoinhibited kinase conformation reveals a salt-bridge switch in kinase activation. Wei Q, Yang S, Li D, Zhang X, Zheng J, Jia Z. Sci Rep 6 28437 (2016)
  26. Regulation of the EphA2 receptor intracellular region by phosphomimetic negative charges in the kinase-SAM linker. Lechtenberg BC, Gehring MP, Light TP, Horne CR, Matsumoto MW, Hristova K, Pasquale EB. Nat Commun 12 7047 (2021)
  27. Letter Stability and crystal structures of His88 mutant human transthyretins. Yokoyama T, Hanawa Y, Obita T, Mizuguchi M. FEBS Lett 591 1862-1871 (2017)
  28. Two-step release of kinase autoinhibition in discoidin domain receptor 1. Sammon D, Hohenester E, Leitinger B. Proc Natl Acad Sci U S A 117 22051-22060 (2020)
  29. Converting a weaker ATP-binding site inhibitor into a potent hetero-bivalent ligand by tethering to a unique peptide sequence derived from the same kinase. Kedika SR, Udugamasooriya DG. Org Biomol Chem 16 6443-6449 (2018)
  30. The intracellular domains of the EphB6 and EphA10 receptor tyrosine pseudokinases function as dynamic signalling hubs. Liang LY, Roy M, Horne CR, Sandow JJ, Surudoi M, Dagley LF, Young SN, Dite T, Babon JJ, Janes PW, Patel O, Murphy JM, Lucet IS. Biochem J 478 3351-3371 (2021)
  31. Crystal structure of the kinase domain of a receptor tyrosine kinase from a choanoflagellate, Monosiga brevicollis. Bajaj T, Kuriyan J, Gee CL. PLoS One 18 e0276413 (2023)


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