Specific Eph receptor-cytoplasmic effector signaling mediated by SAM-SAM domain interactions

  1. Yue Wang
  2. Yuan Shang
  3. Jianchao Li
  4. Weidi Chen
  5. Gang Li
  6. Jun Wan
  7. Wei Liu
  8. Mingjie Zhang  Is a corresponding author
  1. Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, China
  2. Hong Kong University of Science and Technology, Hong Kong
  3. The Hong Kong University of Science and Technology, Hong Kong

Abstract

The Eph receptor tyrosine kinase (RTK) family is the largest subfamily of RTKs playing critical roles in many developmental processes such as tissue patterning, neurogenesis and neuronal circuit formation, angiogenesis, etc. How the 14 Eph proteins, via their highly similar cytoplasmic domains, can transmit diverse and sometimes opposite cellular signals upon engaging ephrins is a major unresolved question. Here we systematically investigated the bindings of each SAM domain of Eph receptors to the SAM domains from SHIP2 and Odin, and uncover a highly specific SAM-SAM interaction-mediated cytoplasmic Eph-effector binding pattern. Comparative X-ray crystallographic studies of several SAM-SAM heterodimer complexes, together with biochemical and cell biology experiments, not only revealed the exquisite specificity code governing Eph/effector interactions but also allowed us to identify SAMD5 as a new Eph binding partner. Finally, these Eph/effector SAM heterodimer structures can explain many Eph SAM mutations identified in patients suffering from cancers and other diseases.

Data availability

The structure factors and the coordinates of the structures reported in this work have been deposited to PDB under the accession codes of 5ZRX, 5ZRY and 5ZRZ for the EphA2/SHIP2, EphA6/Odin and EphA5/SAMD5 complex structures, respectively.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Yue Wang

    Biomedical Research Institute, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, China
    Competing interests
    No competing interests declared.
  2. Yuan Shang

    Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong, Hong Kong
    Competing interests
    No competing interests declared.
  3. Jianchao Li

    Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong, Hong Kong
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8921-1626
  4. Weidi Chen

    Biomedical Research Institute, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, China
    Competing interests
    No competing interests declared.
  5. Gang Li

    Biomedical Research Institute, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, China
    Competing interests
    No competing interests declared.
  6. Jun Wan

    Biomedical Research Institute, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, China
    Competing interests
    No competing interests declared.
  7. Wei Liu

    Biomedical Research Institute, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, China
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8250-2562
  8. Mingjie Zhang

    Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, Hong Kong
    For correspondence
    mzhang@ust.hk
    Competing interests
    Mingjie Zhang, Reviewing editor, <i>eLife</i>.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9404-0190

Funding

Minister of Science and Technology of China (2014CB910204)

  • Mingjie Zhang

Natural Science Foundation of Guangdong Province (2016A030312016)

  • Mingjie Zhang

Shenzhen Basic Research Grant, Shenzhen, China (JCYJ20160229153100269)

  • Wei Liu

National Natural Science Foundation of China (31670765)

  • Wei Liu

Asia Fund for Cancer Research (AFCR17SC01)

  • Mingjie Zhang

Minister of Science and Technology of China (2016YFA0501903)

  • Mingjie Zhang

Shenzhen Basic Research Grant, Shenzhen, China (JCYJ20160427185712266)

  • Wei Liu

Shenzhen Basic Research Grant, Shenzhen, China (JCYJ20170411090807530)

  • Wei Liu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Volker Dötsch, J.W. Goethe-University, Germany

Publication history

  1. Received: February 5, 2018
  2. Accepted: May 10, 2018
  3. Accepted Manuscript published: May 11, 2018 (version 1)
  4. Version of Record published: June 8, 2018 (version 2)

Copyright

© 2018, Wang 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. Yue Wang
  2. Yuan Shang
  3. Jianchao Li
  4. Weidi Chen
  5. Gang Li
  6. Jun Wan
  7. Wei Liu
  8. Mingjie Zhang
(2018)
Specific Eph receptor-cytoplasmic effector signaling mediated by SAM-SAM domain interactions
eLife 7:e35677.
https://doi.org/10.7554/eLife.35677

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