Single-molecule functional anatomy of endogenous HER2-HER3 heterodimers
- Proteina Co Ltd, Republic of Korea
- Korea Advanced Institute of Science and Technology, Republic of Korea
- Seoul National University, Republic of Korea
- Hanyang University, Republic of Korea
Abstract
Human epidermal growth factor receptors (HERs) are the primary targets of many directed cancer therapies. However, the reason a specific dimer of HERs generates a stronger proliferative signal than other permutations remains unclear. Here, we used single-molecule immunoprecipitation to develop a biochemical assay for endogenously-formed, entire HER2-HER3 heterodimers. We observed unexpected, large conformational fluctuations in juxta-membrane and kinase domains of the HER2-HER3 heterodimer. Nevertheless, the individual HER2-HER3 heterodimers catalyze tyrosine phosphorylation at an unusually high rate, while simultaneously interacting with multiple copies of downstream signaling effectors. Our results suggest that the high catalytic rate and multi-tasking capability make a concerted contribution to the strong signaling potency of the HER2-HER3 heterodimers.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files
Article and author information
Author details
Funding
National Research Foundation of Korea (NRF-2011-0018352)
- Tae-Young Yoon
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Yibing Shan, DE Shaw Research, United States
Version history
- Received: November 25, 2019
- Accepted: April 7, 2020
- Accepted Manuscript published: April 8, 2020 (version 1)
- Version of Record published: April 22, 2020 (version 2)
- Version of Record updated: July 7, 2020 (version 3)
Copyright
© 2020, Choi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Single-molecule functional anatomy of endogenous HER2-HER3 heterodimers
eLife 9:e53934.
https://doi.org/10.7554/eLife.53934
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