PDF(Pubmed)
Abstract：
NF2 (moesin-ezrin-radixin-like [MERLIN] tumor suppressor) is frequently inactivated in cancer, where its NF2 tumor suppressor functionality is tightly coupled to protein conformation. How NF2 conformation is regulated and how NF2 conformation influences tumor suppressor activity is a largely open question. Here, we systematically characterized three NF2 conformation-dependent protein interactions utilizing deep mutational scanning interaction perturbation analyses. We identified two regions in NF2 with clustered mutations which affected conformation-dependent protein interactions. NF2 variants in the F2-F3 subdomain and the α3H helix region substantially modulated NF2 conformation and homomerization. Mutations in the F2-F3 subdomain altered proliferation in three cell lines and matched patterns of disease mutations in NF2 related-schwannomatosis. This study highlights the power of systematic mutational interaction perturbation analysis to identify missense variants impacting NF2 conformation and provides insight into NF2 tumor suppressor function.
摘要：
NF2（moesin-ezrin-radixin-like[MERLIN]肿瘤抑制剂）在癌症中经常失活，其中它的NF2肿瘤抑制功能与蛋白质构象紧密偶联。NF2构象如何被调节以及NF2构象如何影响肿瘤抑制活性是一个很大的悬而未决的问题。这里,我们利用深度突变扫描相互作用扰动分析系统地表征了三种NF2构象依赖性蛋白质相互作用。我们在NF2中鉴定了具有影响构象依赖性蛋白质相互作用的成簇突变的两个区域。F2-F3亚结构域和α3H螺旋区中的NF2变体基本上调节NF2构象和同种化。F2-F3亚结构域的突变改变了三种细胞系的增殖，并改变了NF2相关神经鞘瘤病的疾病突变模式。这项研究强调了系统突变相互作用扰动分析的力量，以识别影响NF2构象的错义变体，并提供了对NF2肿瘤抑制功能的见解。
