Structural basis for autoinhibition of the Ephb2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region - PubMed (original) (raw)

Comparative Study

. 2001 Sep 21;106(6):745-57.

doi: 10.1016/s0092-8674(01)00496-2.

Affiliations

• PMID: 11572780
• DOI: 10.1016/s0092-8674(01)00496-2

Free article

Comparative Study

Structural basis for autoinhibition of the Ephb2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region

L E Wybenga-Groot et al. Cell. 2001.

Free article

Abstract

The Eph receptor tyrosine kinase family is regulated by autophosphorylation within the juxtamembrane region and the kinase activation segment. We have solved the X-ray crystal structure to 1.9 A resolution of an autoinhibited, unphosphorylated form of EphB2 comprised of the juxtamembrane region and the kinase domain. The structure, supported by mutagenesis data, reveals that the juxtamembrane segment adopts a helical conformation that distorts the small lobe of the kinase domain, and blocks the activation segment from attaining an activated conformation. Phosphorylation of conserved juxtamembrane tyrosines would relieve this autoinhibition by disturbing the association of the juxtamembrane segment with the kinase domain, while liberating phosphotyrosine sites for binding SH2 domains of target proteins. We propose that the autoinhibitory mechanism employed by EphB2 is a more general device through which receptor tyrosine kinases are controlled.

PubMed Disclaimer

Similar articles

• Replacing two conserved tyrosines of the EphB2 receptor with glutamic acid prevents binding of SH2 domains without abrogating kinase activity and biological responses.
  Zisch AH, Pazzagli C, Freeman AL, Schneller M, Hadman M, Smith JW, Ruoslahti E, Pasquale EB. Zisch AH, et al. Oncogene. 2000 Jan 13;19(2):177-87. doi: 10.1038/sj.onc.1203304. Oncogene. 2000. PMID: 10644995
• 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. Davis TL, et al. Structure. 2008 Jun;16(6):873-84. doi: 10.1016/j.str.2008.03.008. Structure. 2008. PMID: 18547520
• Multiple in vivo tyrosine phosphorylation sites in EphB receptors.
  Kalo MS, Pasquale EB. Kalo MS, et al. Biochemistry. 1999 Oct 26;38(43):14396-408. doi: 10.1021/bi991628t. Biochemistry. 1999. PMID: 10572014
• Complex formation between EphB2 and Src requires phosphorylation of tyrosine 611 in the EphB2 juxtamembrane region.
  Zisch AH, Kalo MS, Chong LD, Pasquale EB. Zisch AH, et al. Oncogene. 1998 May;16(20):2657-70. doi: 10.1038/sj.onc.1201823. Oncogene. 1998. PMID: 9632142
• Structure and mechanism of the G protein-coupled receptor kinases.
  Inglese J, Freedman NJ, Koch WJ, Lefkowitz RJ. Inglese J, et al. J Biol Chem. 1993 Nov 15;268(32):23735-8. J Biol Chem. 1993. PMID: 8226899 Review. No abstract available.

Cited by

• 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. Forse GJ, et al. PLoS One. 2015 May 20;10(5):e0127081. doi: 10.1371/journal.pone.0127081. eCollection 2015. PLoS One. 2015. PMID: 25993310 Free PMC article.
• Axl is essential for VEGF-A-dependent activation of PI3K/Akt.
  Ruan GX, Kazlauskas A. Ruan GX, et al. EMBO J. 2012 Apr 4;31(7):1692-703. doi: 10.1038/emboj.2012.21. Epub 2012 Feb 10. EMBO J. 2012. PMID: 22327215 Free PMC article.
• Autoinhibition of Jak2 tyrosine kinase is dependent on specific regions in its pseudokinase domain.
  Saharinen P, Vihinen M, Silvennoinen O. Saharinen P, et al. Mol Biol Cell. 2003 Apr;14(4):1448-59. doi: 10.1091/mbc.e02-06-0342. Mol Biol Cell. 2003. PMID: 12686600 Free PMC article.
• A regulatory role of membrane by direct modulation of the catalytic kinase domain.
  Prakash P. Prakash P. Small GTPases. 2021 Jul;12(4):246-256. doi: 10.1080/21541248.2020.1788886. Epub 2020 Jul 14. Small GTPases. 2021. PMID: 32663062 Free PMC article. Review.
• The tethered configuration of the EGF receptor extracellular domain exerts only a limited control of receptor function.
  Mattoon D, Klein P, Lemmon MA, Lax I, Schlessinger J. Mattoon D, et al. Proc Natl Acad Sci U S A. 2004 Jan 27;101(4):923-8. doi: 10.1073/pnas.0307286101. Epub 2004 Jan 19. Proc Natl Acad Sci U S A. 2004. PMID: 14732693 Free PMC article.

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Elsevier Science

• Other Literature Sources

  • H1 Connect
  • The Lens - Patent Citations Database

• Molecular Biology Databases

  • GlyGen glycoinformatics resource
  • Saccharomyces Genome Database

• Miscellaneous

  • NCI CPTAC Assay Portal