Investigating structure function relationships in the NOTCH family through large-scale somatic DNA sequencing studies
Investigating structure function relationships in the NOTCH family through large-scale somatic DNA sequencing studies
复制标题
通过大规模体细胞 DNA 测序研究研究 NOTCH 家族的结构功能关系
DOI：
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
B. Hall
中科院分区：
文献类型：
--
作者：
Michael W. J. Hall;David Shorthouse;P. Jones;B. Hall
近年来，高灵敏度DNA测序技术的发展已经在老化的正常组织中检测到大量的基因错义突变，包括NOTCH1和2。驱动突变通过对野生型细胞和替代突变的选择优势在组织中持续和繁殖。这个选择过程可以被认为是一个大规模的，体内筛选突变，增加克隆适应性。因此，在单个基因中观察到的特定错义突变可能为我们了解结构-功能关系提供了见解。本研究表明，人食管上皮NOTCH1和NOTCH2的正选择错义突变主要通过蛋白质错误折叠导致失活。一旦这些突变被排除，我们进一步发现在配体结合界面和钙结合位点的选择有统计学意义的证据。在这项研究中，我们观察到EGF12在配体界面上选择EGF11的更强证据，这表明在该组织中，EGF12可能在配体相互作用中发挥更重要的作用。最后，我们展示了NOTCH1跨膜螺旋中的突变热点是如何通过高突变率和残基守恒的交集而产生的。总之，这些见解提供了通过体内突变体选择来理解蛋白质功能机制的途径。
The recent development of highly sensitive DNA sequencing techniques has detected large numbers of missense mutations of genes, including NOTCH1 and 2, in ageing normal tissues. Driver mutations persist and propagate in the tissue through a selective advantage over both wild-type cells and alternative mutations. This process of selection can be considered as a large scale, in vivo screen for mutations that increase clone fitness. It follows that the specific missense mutations that are observed in individual genes may offer us insights into the structure-function relationships. Here we show that the positively selected missense mutations in NOTCH1 and NOTCH2 in human oesophageal epithelium cause inactivation predominantly through protein misfolding. Once these mutations are excluded, we further find statistically significant evidence for selection at the ligand binding interface and calcium binding sites. In this, we observe stronger evidence of selection at the ligand interface on EGF12 over EGF11, suggesting that in this tissue EGF12 may play a more important role in ligand interaction. Finally, we show how a mutation hotspot in the NOTCH1 transmembrane helix arises through the intersection of both a high mutation rate and residue conservation. Together these insights offer a route to understanding the mechanism of protein function through in vivo mutant selection.
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影响因子：
7
作者：
Siepel, A;Bejerano, G;Haussler, D
通讯作者：
Haussler, D
DOI：
10.1126/science.1261093
发表时间：
2015-02-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Luca VC;Jude KM;Pierce NW;Nachury MV;Fischer S;Garcia KC
通讯作者：
Garcia KC
DOI：
10.1146/annurev-pathol-052016-100127
发表时间：
2017-01-24
期刊：
Annual review of pathology
影响因子：
--
作者：
Aster JC;Pear WS;Blacklow SC
通讯作者：
Blacklow SC
影响因子：
5.6
作者：
Ittisoponpisan, Sirawit;Islam, Suhail A.;Sternberg, Michael J. E.
通讯作者：
Sternberg, Michael J. E.
影响因子：
7
作者：
Kent, WJ;Sugnet, CW;Haussler, D
通讯作者：
Haussler, D