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Structure. 2018 Feb 6;26(2):270-281.e4. doi: 10.1016/j.str.2017.12.012. Epub 2018 Jan 18.

Regulation of Kinase Activity in the Caenorhabditis elegans EGF Receptor, LET-23.

Author information

1
Cardiovascular Research Institute, University of California - San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California - San Francisco, San Francisco, CA 94158, USA.
2
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA; Cancer Biology Institute, Yale University, West Haven, CT 06516, USA.
3
Cardiovascular Research Institute, University of California - San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California - San Francisco, San Francisco, CA 94158, USA. Electronic address: natalia.jura@ucsf.edu.

Abstract

In the active HER receptor dimers, kinases play distinct roles; one is the catalytically active kinase and the other is its allosteric activator. This specialization enables signaling by the catalytically inactive HER3, which functions exclusively as an allosteric activator upon heterodimerization with other HER receptors. It is unclear whether the allosteric activation mechanism evolved before HER receptors functionally specialized. We determined the crystal structure of the kinase domain of the only EGF receptor in Caenorhabditis elegans, LET-23. Our structure of a non-human EGFR kinase reveals autoinhibitory features conserved in the human counterpart. Strikingly, mutations within the putative allosteric dimer interface abrogate activity of the isolated LET-23 kinase and of the full-length receptor despite these regions being only partially conserved with human EGFR. Our results indicate that ancestral EGFRs have built-in features that poise them for allosteric activation that could facilitate emergence of the catalytically dead, yet functional, orthologs.

KEYWORDS:

EGFR; ERBB receptors; HER receptors; LET-23; allosteric kinase activation; asymmetric dimerization; kinase activation; kinase structure; receptor tyrosine kinase signaling

PMID:
29358026
PMCID:
PMC5803352
DOI:
10.1016/j.str.2017.12.012
[Indexed for MEDLINE]
Free PMC Article

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