The EGFR (epidermal growth factor receptor)/ErbB/HER (human EGFR) family of kinases contains four homologous receptor tyrosine kinases that are important regulatory elements in key signalling pathways. To elucidate the atomistic mechanisms of dimerization-dependent activation in the ErbB family, we have performed molecular dynamics simulations of the intracellular kinase domains of three members of the ErbB family (those with known kinase activity), namely EGFR, ErbB2 (HER2) and ErbB4 (HER4), in different molecular contexts: monomer against dimer and wild-type against mutant. Using bioinformatics and fluctuation analyses of the molecular dynamics trajectories, we relate sequence similarities to correspondence of specific bond-interaction networks and collective dynamical modes. We find that in the active conformation of the ErbB kinases, key subdomain motions are co-ordinated through conserved hydrophilic interactions: activating bond-networks consisting of hydrogen bonds and salt bridges. The inactive conformations also demonstrate conserved bonding patterns (albeit less extensive) that sequester key residues and disrupt the activating bond network. Both conformational states have distinct hydrophobic advantages through context-specific hydrophobic interactions. We show that the functional (activating) asymmetric kinase dimer interface forces a corresponding change in the hydrophobic and hydrophilic interactions that characterize the inactivating bond network, resulting in motion of the αC-helix through allostery. Several of the clinically identified activating kinase mutations of EGFR act in a similar fashion to disrupt the inactivating bond network. The present molecular dynamics study reveals a fundamental difference in the sequence of events in EGFR activation compared with that described for the Src kinase Hck.
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Research Article|
May 13 2011
Molecular dynamics analysis of conserved hydrophobic and hydrophilic bond-interaction networks in ErbB family kinases
Andrew J. Shih;
Andrew J. Shih
*Department of Bioengineering, University of Pennsylvania, 210 S. 33 Street, 240 Skirkanich Hall, Philadelphia, PA 19104, U.S.A.
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Shannon E. Telesco;
Shannon E. Telesco
*Department of Bioengineering, University of Pennsylvania, 210 S. 33 Street, 240 Skirkanich Hall, Philadelphia, PA 19104, U.S.A.
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Sung-Hee Choi;
Sung-Hee Choi
†Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 809C Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104, U.S.A.
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Mark A. Lemmon;
Mark A. Lemmon
†Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 809C Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104, U.S.A.
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Ravi Radhakrishnan
Ravi Radhakrishnan
1
*Department of Bioengineering, University of Pennsylvania, 210 S. 33 Street, 240 Skirkanich Hall, Philadelphia, PA 19104, U.S.A.
1To whom correspondence should be addressed (email rradhak@seas.upenn.edu).
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Publisher: Portland Press Ltd
Received:
November 02 2010
Revision Received:
February 21 2011
Accepted:
March 22 2011
Accepted Manuscript online:
March 22 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 436 (2): 241–251.
Article history
Received:
November 02 2010
Revision Received:
February 21 2011
Accepted:
March 22 2011
Accepted Manuscript online:
March 22 2011
Citation
Andrew J. Shih, Shannon E. Telesco, Sung-Hee Choi, Mark A. Lemmon, Ravi Radhakrishnan; Molecular dynamics analysis of conserved hydrophobic and hydrophilic bond-interaction networks in ErbB family kinases. Biochem J 1 June 2011; 436 (2): 241–251. doi: https://doi.org/10.1042/BJ20101791
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