Structural insights into Ras regulation by SIN1.
Structural insights into Ras regulation by SIN1.
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DOI：
10.1073/pnas.2119990119
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发表时间：
2022-05-10
影响因子：
11.1
通讯作者：
Zhou C
中科院分区：
文献类型：
--
作者：
Zheng Y;Ding L;Meng X;Potter M;Kearney AL;Zhang J;Sun J;James DE;Yang G;Zhou C
Both the mTORC2 and Ras-ERK pathways respond to growth factor stimulation and play critical roles in cell growth and proliferation, disarray of these pathways leads to many diseases, especially cancer. These two signaling pathways crosstalk at many levels; recently it's become clear that the SIN1 component of mTORC2 could interact with Ras family small GTPases, but how these two proteins interact at the molecular level and the functional outcomes of this interaction remain to be addressed. In this work we determined the high-resolution structure of Ras-SIN1 complexes and revealed the detailed interaction mechanism. We also showed that Ras-SIN1 association inhibits insulin-induced ERK activation. Insights from this work could improve our understanding of the disease-causing mechanism of errant mTORC2 or Ras proteins. Over the years it has been established that SIN1, a key component of mTORC2, could interact with Ras family small GTPases through its Ras-binding domain (RBD). The physical association of Ras and SIN1/mTORC2 could potentially affect both mTORC2 and Ras-ERK pathways. To decipher the precise molecular mechanism of this interaction, we determined the high-resolution structures of HRas/KRas-SIN1 RBD complexes, showing the detailed interaction interface. Mutation of critical interface residues abolished Ras-SIN1 interaction and in SIN1 knockout cells we demonstrated that Ras-SIN1 association promotes SGK1 activity but inhibits insulin-induced ERK activation. With structural comparison and competition fluorescence resonance energy transfer (FRET) assays we showed that HRas-SIN1 RBD association is much weaker than HRas-Raf1 RBD but is slightly stronger than HRas-PI3K RBD interaction, providing a possible explanation for the different outcome of insulin or EGF stimulation. We also found that SIN1 isoform lacking the PH domain binds stronger to Ras than other longer isoforms and the PH domain appears to have an inhibitory effect on Ras-SIN1 binding. In addition, we uncovered a Ras dimerization interface that could be critical for Ras oligomerization. Our results advance our understanding of Ras-SIN1 association and crosstalk between growth factor-stimulated pathways.
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影响因子：
4
作者：
Hobbs, G. Aaron;Der, Channing J.;Rossman, Kent L.
通讯作者：
Rossman, Kent L.
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
3.5
作者：
Fu W;Hall MN
通讯作者：
Hall MN
DOI：
10.1073/pnas.1914076117
发表时间：
2020-06-02
影响因子：
11.1
作者：
Fang, Zhenhao;Lee, Ki-Young;Marshall, Christopher B.
通讯作者：
Marshall, Christopher B.
影响因子：
64.5
作者：
Jacinto, Estela;Facchinetti, Valeria;Su, Bing
通讯作者：
Su, Bing