Single-molecule functional anatomy of endogenous HER2-HER3 heterodimers

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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.

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All data generated or analysed during this study are included in the manuscript and supporting files

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Byoungsan Choi

Proteina R&D center, Proteina Co Ltd, Seoul, Republic of Korea

Competing interests
Byoungsan Choi, B.C. and T.-Y.Y. filed a patent on these findings (10-2018-0125506). T.-Y.Y. is co-founder of Proteina. B.C. is now a senior scientist at Proteina..
Minkwon Cha

Department of Physics, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea

Competing interests
No competing interests declared.
Gee Sung Eun

School of Biological Sciences and Institute for Molecular Biology and Genetics, Seoul National University, Seoul, Republic of Korea

Competing interests
No competing interests declared.
Dae Hee Lee

Proteina R&D center, Proteina Co Ltd, Seoul, Republic of Korea

Competing interests
No competing interests declared.
Seul Lee

Proteina R&D center, Proteina Co Ltd, Seoul, Republic of Korea

Competing interests
No competing interests declared.
Muhammad Ehsan

Department of Bionanotechnology, Hanyang University, Ansan, Republic of Korea

Competing interests
No competing interests declared.
Pil Seok Chae

Department of Bionanotechnology, Hanyang University, Ansan, Republic of Korea

Competing interests
No competing interests declared.
Won Do Heo

Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea

Competing interests
No competing interests declared.
YongKeun Park

Department of Physics, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0003-0528-6661
Tae-Young Yoon

School of Biological Sciences and Institute for Molecular Biology and Genetics, Seoul National University, Seoul, Republic of Korea

For correspondence
tyyoon@snu.ac.kr

Competing interests
Tae-Young Yoon, B.C. and T.-Y.Y. filed a patent on these findings (10-2018-0125506). T.-Y.Y. is co-founder of Proteina. B.C. is now a senior scientist at Proteina..

"This ORCID iD identifies the author of this article:" 0000-0002-5184-7725

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.

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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.