Single-molecule functional anatomy of endogenous HER2-HER3 heterodimers

  1. Byoungsan Choi
  2. Minkwon Cha
  3. Gee Sung Eun
  4. Dae Hee Lee
  5. Seul Lee
  6. Muhammad Ehsan
  7. Pil Seok Chae
  8. Won Do Heo
  9. YongKeun Park
  10. Tae-Young Yoon  Is a corresponding author
  1. Proteina Co Ltd, Republic of Korea
  2. Korea Advanced Institute of Science and Technology, Republic of Korea
  3. Seoul National University, Republic of Korea
  4. 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.

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

Article and author information

Author details

  1. 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..
  2. Minkwon Cha

    Department of Physics, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    Competing interests
    No competing interests declared.
  3. 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.
  4. Dae Hee Lee

    Proteina R&D center, Proteina Co Ltd, Seoul, Republic of Korea
    Competing interests
    No competing interests declared.
  5. Seul Lee

    Proteina R&D center, Proteina Co Ltd, Seoul, Republic of Korea
    Competing interests
    No competing interests declared.
  6. Muhammad Ehsan

    Department of Bionanotechnology, Hanyang University, Ansan, Republic of Korea
    Competing interests
    No competing interests declared.
  7. Pil Seok Chae

    Department of Bionanotechnology, Hanyang University, Ansan, Republic of Korea
    Competing interests
    No competing interests declared.
  8. Won Do Heo

    Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    Competing interests
    No competing interests declared.
  9. YongKeun Park

    Department of Physics, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0528-6661
  10. 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..
    ORCID icon "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.

Reviewing Editor

  1. Yibing Shan, DE Shaw Research, United States

Version history

  1. Received: November 25, 2019
  2. Accepted: April 7, 2020
  3. Accepted Manuscript published: April 8, 2020 (version 1)
  4. Version of Record published: April 22, 2020 (version 2)
  5. 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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  1. Byoungsan Choi
  2. Minkwon Cha
  3. Gee Sung Eun
  4. Dae Hee Lee
  5. Seul Lee
  6. Muhammad Ehsan
  7. Pil Seok Chae
  8. Won Do Heo
  9. YongKeun Park
  10. Tae-Young Yoon
(2020)
Single-molecule functional anatomy of endogenous HER2-HER3 heterodimers
eLife 9:e53934.
https://doi.org/10.7554/eLife.53934

Share this article

https://doi.org/10.7554/eLife.53934

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