4.8 Article

Double inhibition and activation mechanisms of Ephexin family RhoGEFs

出版社

NATL ACAD SCIENCES
DOI: 10.1073/pnas.2024465118

关键词

Ephexin; RhoGEF; autoinhibition; crystal structure

资金

  1. National Key R&D Program of China [2018YFA0507900, 2019YFA0508402]
  2. National Natural Science Foundation of China [U2032122, 31770779, 31670734, 91953110]
  3. Science and Technology Commission of Shanghai Municipality [20S11900200]
  4. University of Science and Technology of China Research Funds of Double First-Class Initiative [YD9100002006]
  5. Fundamental Research Funds for the Central Universities [WK9100000029]
  6. Chinese Academy of Sciences Pioneer Hundred Talents Program

向作者/读者索取更多资源

Ephexin family guanine nucleotide exchange factors (GEFs) play critical roles in cellular processes, cancers, and brain disorders by transferring signals from Eph receptors to Rho GTPases. The study reveals that Ephexin4 utilizes both N- and C-terminal inhibitory modes for complete autoinhibition, which can be relieved through phosphorylation and PDZ protein binding, providing insights into the regulation of Ephexin4 GEF activity.
Ephexin family guanine nucleotide exchange factors (GEFs) transfer signals from Eph tyrosine kinase receptors to Rho GTPases, which play critical roles in diverse cellular processes, as well as cancers and brain disorders. Here, we elucidate the molecular basis underlying inhibition and activation of Ephexin family RhoGEFs. The crystal structures of partially and fully autoinhibited Ephexin4 reveal that the complete autoinhibition requires both N- and C-terminal inhibitory modes, which can operate independently to impede Ras homolog family member G (RhoG) access. This double inhibition mechanism is commonly employed by other Ephexins and SGEF, another RhoGEF for RhoG. Structural, enzymatic, and cell biological analyses show that phosphorylation of a conserved tyrosine residue in its N-terminal inhibitory domain and association of PDZ proteins with its C-terminal PDZ-binding motif may respectively relieve the two autoinhibitory modes in Ephexin4. Our study provides a mechanistic framework for understanding the fine-tuning regulation of Ephexin4 GEF activity and offers possible clues for its pathological dysfunction.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.8
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据