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

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...

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Main Authors:	Huang, Yongjian, Bharill, Shashank, Karandur, Deepti, Peterson, Sean M, Marita, Morgan, Shi, Xiaojun, Kaliszewski, Megan J, Smith, Adam W, Isacoff, Ehud Y, Kuriyan, John
Format:	Online
Language:	English
Published:	eLife Sciences Publications, Ltd 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4902571/

id	pubmed-4902571
recordtype	oai_dc
spelling	pubmed-49025712016-06-13 Molecular basis for multimerization in the activation of the epidermal growth factor receptor Huang, Yongjian Bharill, Shashank Karandur, Deepti Peterson, Sean M Marita, Morgan Shi, Xiaojun Kaliszewski, Megan J Smith, Adam W Isacoff, Ehud Y Kuriyan, John Biochemistry 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. eLife Sciences Publications, Ltd 2016-03-28 /pmc/articles/PMC4902571/ /pubmed/27017828 http://dx.doi.org/10.7554/eLife.14107 Text en © 2016, Huang et al http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Huang, Yongjian Bharill, Shashank Karandur, Deepti Peterson, Sean M Marita, Morgan Shi, Xiaojun Kaliszewski, Megan J Smith, Adam W Isacoff, Ehud Y Kuriyan, John
spellingShingle	Huang, Yongjian Bharill, Shashank Karandur, Deepti Peterson, Sean M Marita, Morgan Shi, Xiaojun Kaliszewski, Megan J Smith, Adam W Isacoff, Ehud Y Kuriyan, John Molecular basis for multimerization in the activation of the epidermal growth factor receptor
author_facet	Huang, Yongjian Bharill, Shashank Karandur, Deepti Peterson, Sean M Marita, Morgan Shi, Xiaojun Kaliszewski, Megan J Smith, Adam W Isacoff, Ehud Y Kuriyan, John
author_sort	Huang, Yongjian
title	Molecular basis for multimerization in the activation of the epidermal growth factor receptor
title_short	Molecular basis for multimerization in the activation of the epidermal growth factor receptor
title_full	Molecular basis for multimerization in the activation of the epidermal growth factor receptor
title_fullStr	Molecular basis for multimerization in the activation of the epidermal growth factor receptor
title_full_unstemmed	Molecular basis for multimerization in the activation of the epidermal growth factor receptor
title_sort	molecular basis for multimerization in the activation of the epidermal growth factor receptor
description	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.
publisher	eLife Sciences Publications, Ltd
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4902571/
_version_	1613593084874981376

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

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