Specific Eph receptor-cytoplasmic effector signaling mediated by SAM-SAM domain interactions
- Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, China
- Hong Kong University of Science and Technology, Hong Kong
- 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.
Article and author information
Author details
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.
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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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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