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特定的 Eph 受体-细胞质效应子信号通过 SAM-SAM 结构域相互作用进行传递。

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

机构信息

Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, China.

Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Kowloon, China.

出版信息

Elife. 2018 May 11;7:e35677. doi: 10.7554/eLife.35677.

DOI:10.7554/eLife.35677
PMID:29749928
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5993539/
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.

摘要

Eph 受体酪氨酸激酶 (RTK) 家族是 RTK 家族中最大的亚家族，在许多发育过程中发挥着关键作用，如组织模式形成、神经发生和神经元回路形成、血管生成等。14 种 Eph 蛋白如何通过其高度相似的细胞质结构域，在与 ephrins 结合时传递不同的、有时甚至相反的细胞信号，这是一个尚未解决的主要问题。在这里，我们系统地研究了 Eph 受体的每个 SAM 结构域与 SHIP2 和 Odin 的 SAM 结构域的结合情况，并揭示了一种高度特异性的 SAM-SAM 相互作用介导的细胞质 Eph 效应物结合模式。对几种 SAM-SAM 异源二聚体复合物的比较 X 射线晶体学研究，以及生化和细胞生物学实验，不仅揭示了 Eph/效应物相互作用的精细特异性编码，还使我们能够鉴定 SAMD5 为 Eph 的新结合伴侣。最后，这些 Eph/效应物 SAM 异源二聚体结构可以解释许多在患有癌症和其他疾病的患者中发现的 Eph SAM 突变。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed0f/5993539/b1a291645b3a/elife-35677-resp-fig2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed0f/5993539/1f9f407e8e6b/elife-35677-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed0f/5993539/6251fcda9eb2/elife-35677-resp-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed0f/5993539/b1a291645b3a/elife-35677-resp-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed0f/5993539/4607151e7d9f/elife-35677-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed0f/5993539/cfd6e8697d88/elife-35677-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed0f/5993539/dfcbd19c5f13/elife-35677-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed0f/5993539/ad3fe4d79184/elife-35677-fig2-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed0f/5993539/c49f2c807a3a/elife-35677-fig2-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed0f/5993539/21875110371e/elife-35677-fig2-figsupp4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed0f/5993539/fb93fdcdd698/elife-35677-fig2-figsupp5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed0f/5993539/cba8a0e03a44/elife-35677-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed0f/5993539/abd30f2cdd1b/elife-35677-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed0f/5993539/dcb28a7446ba/elife-35677-fig3-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed0f/5993539/af192a7e6c75/elife-35677-fig4.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed0f/5993539/b1a291645b3a/elife-35677-resp-fig2.jpg

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