Molecular basis for multimerization in the activation of the epidermal growth factor receptor.

ELife
Yongjian HuangJohn Kuriyan

Abstract

The epidermal growth factor receptor (EGFR) is activated by dimerization, but activation also generates higher-order multimers, whose nature and function are poorly understood. We have characterized ligand-induced dimerization and multimerization of EGFR using single-molecule analysis, and show that multimerization can be blocked by mutations in a specific region of Domain IV of the extracellular module. These mutations reduce autophosphorylation of the C-terminal tail of EGFR and attenuate phosphorylation of phosphatidyl inositol 3-kinase, which is recruited by EGFR. The catalytic activity of EGFR is switched on through allosteric activation of one kinase domain by another, and we show that if this is restricted to dimers, then sites in the tail that are proximal to the kinase domain are phosphorylated in only one subunit. We propose a structural model for EGFR multimerization through self-association of ligand-bound dimers, in which the majority of kinase domains are activated cooperatively, thereby boosting tail phosphorylation.

References

Aug 1, 1994·Molecular and Cellular Biology·A G BatzerJ Schlessinger
Jan 15, 1997·The EMBO Journal·M A LemmonJ Schlessinger
Apr 24, 1999·FEBS Letters·J T JonesM X Sliwkowski
Mar 17, 2001·Nature Reviews. Molecular Cell Biology·Y Yarden, M X Sliwkowski
Oct 1, 1984·The Journal of Chemical Physics·D J DeFrees, A D McLean
Dec 14, 2001·The Journal of Biological Chemistry·Jeannine M MendrolaMark A Lemmon
Aug 28, 2002·The Journal of Biological Chemistry·Jennifer StamosCharles Eigenbrot
Sep 14, 2002·Proceedings of the National Academy of Sciences of the United States of America·Alois SonnleitnerEhud Y Isacoff
Dec 4, 2002·Proceedings of the National Academy of Sciences of the United States of America·Sarel J FleishmanNir Ben-Tal
Mar 22, 2003·Experimental Cell Research·Ami CitriYosef Yarden
Aug 27, 2004·Proceedings of the National Academy of Sciences of the United States of America·William PaoHarold Varmus
Oct 27, 2004·Advances in Protein Chemistry·Daniel J Leahy
Aug 23, 2005·Biophysical Journal·Barbara K MüllerDon C Lamb
Oct 4, 2005·Journal of Computational Chemistry·David A CaseRobert J Woods
Jan 11, 2007·The Journal of Chemical Physics·Giovanni BussiMichele Parrinello
Mar 21, 2007·Nature Methods·Maximilian H Ulbrich, Ehud Y Isacoff
Jun 16, 2007·The Journal of Physical Chemistry. B·Siewert J MarrinkAlex H de Vries
Aug 19, 2007·Structure·Jessica P DawsonMark A Lemmon
Mar 13, 2008·Structure·Chen QiuDaniel J Leahy
Oct 22, 2008·Growth Factors·Andrew H A ClaytonAntony W Burgess
Dec 17, 2008·Nature·Alexei V KorennykhPeter Walter
Jun 30, 2009·Molecular Cell·Monica Red BrewerGraham Carpenter
Dec 17, 2009·Proceedings of the National Academy of Sciences of the United States of America·Natalia JuraJohn Kuriyan
Mar 31, 2010·Proceedings of the National Academy of Sciences of the United States of America·Fumin ShiMark A Lemmon
May 18, 2010·Journal of Molecular Biology·Konstantin S MineevAlexander S Arseniev
Sep 4, 2010·Proceedings of the National Academy of Sciences of the United States of America·Peter NagyDonna J Arndt-Jovin
Sep 14, 2010·Wiley Interdisciplinary Reviews. Systems Biology and Medicine·Michelle A Digman, Enrico Gratton
Apr 2, 2011·The Journal of Biological Chemistry·Kathleen AertgeertsSatoshi Sogabe

❮ Previous
Next ❯

Citations

Mar 4, 2017·Materials Science & Engineering. C, Materials for Biological Applications·Eduardo AnituaGorka Orive
Jul 13, 2018·The Journal of Biological Chemistry·Jennifer L Macdonald-Obermann, Linda J Pike
Mar 10, 2019·Nature Reviews. Drug Discovery·Jennifer E Kung, Natalia Jura
Nov 1, 2016·Nature Communications·Sarah R NeedhamMarisa L Martin-Fernandez
Mar 25, 2017·Scientific Reports·Xiaojun ShiAdam W Smith
Nov 20, 2019·European Biophysics Journal : EBJ·Noga Kozer, Andrew H A Clayton
Dec 28, 2019·The Journal of Biological Chemistry·Justin M Westerfield, Francisco N Barrera
Jul 31, 2020·The Journal of Biological Chemistry·Patrick O ByrneDaniel J Leahy
Feb 6, 2017·PLoS Computational Biology·Jerome M KarpDavid Cowburn
May 10, 2017·Proteins·Maryam Azimzadeh IraniChandra Verma
Aug 15, 2018·Proceedings of the National Academy of Sciences of the United States of America·Zheng Ruan, Natarajan Kannan
Apr 26, 2019·Proceedings of the National Academy of Sciences of the United States of America·Qi WangDavid E Shaw
Jul 31, 2020·Nature·Steven M BanikCarolyn R Bertozzi
Sep 28, 2017·Growth Factors·Shabnam KhatibiAntony W Burgess
Nov 21, 2019·Scientific Reports·David S CorcoranBirgit Leitinger
Jun 6, 2019·Methods and Protocols·David T Clarke, Marisa L Martin-Fernandez
Feb 12, 2017·The Journal of Biological Chemistry·Christopher KingKalina Hristova
Jul 22, 2020·Annual Review of Cell and Developmental Biology·Aneta Koseska, Philippe I H Bastiaens
Oct 13, 2020·The Biochemical Journal·Monica Gonzalez-MagaldiDaniel J Leahy
Jul 12, 2019·Biochimica Et Biophysica Acta. Biomembranes·Deo R SinghKalina Hristova
Oct 3, 2020·Angewandte Chemie·Peng Shi, Yong Wang
Jan 27, 2021·Proceedings of the National Academy of Sciences of the United States of America·Zhongwen ChenJay T Groves
Nov 4, 2020·Nature Nanotechnology·Elena AmbrosettiAna I Teixeira
Jan 7, 2017·Journal of Cardiovascular Pharmacology·Laurel A GrisantiDouglas G Tilley
Mar 7, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Nichole E M KaufmanMaria da Graça H Vicente
Jan 1, 2018·Nature Physics·Joe Chin-Hun KuoMatthew J Paszek
Apr 24, 2021·Journal of Molecular Biology·Michael D Paul, Kalina Hristova
May 13, 2021·ACS Chemical Neuroscience·Omid Tavassoly, Iman Tavassoly
Aug 10, 2021·Frontiers in Oncology·Weili MinYang Zhao
Mar 20, 2018·Biochemistry·Steven D QuinnGabriela S Schlau-Cohen

❮ Previous
Next ❯

Methods Mentioned

BETA
fluorescence
cross-correlation spectroscopy
transfection
FACS
glycosylation
NMR
Fluorescence correlation
flow cytometry

Software Mentioned

NIS
Cluspro
Nikon
PyMOL Molecular Graphics System
nsane
GROMACS
AMBER
Martinize
elements
PyMOL

Related Concepts

Related Feeds

AKT Pathway

This feed focuses on the AKT serine/threonine kinase, which is an important signaling pathway involved in processes such as glucose metabolism and cell survival.