文章基本信息

标题：KRAS Ubiquitination at Lysine 104 Retains Exchange Factor Regulation by Dynamically Modulating the Conformation of the Interface
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作者：Guowei Yin ; Jerry Zhang ; Vinay Nair 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2020
卷号：23
期号：9
页码：1-26
DOI：10.1016/j.isci.2020.101448
语种：English
出版社：Elsevier
摘要：SummaryRAS proteins function as highly regulated molecular switches that control cellular growth. In addition to regulatory proteins, RAS undergoes a number of posttranslational modifications (PTMs) that regulate its activity. Lysine 104, a hot spot for multiple PTMs, is a highly conserved residue that forms key interactions that stabilize the RAS helix-2(H2)/helix-3(H3) interface. Mutation at 104 attenuates interaction with guanine nucleotide exchange factors (GEFs), whereas ubiquitination at lysine 104 retains GEF regulation. To elucidate how ubiquitination modulates RAS function, we generated monoubiquitinated KRAS at 104 using chemical biology approaches and conducted biochemical, NMR, and computational analyses. We find that ubiquitination promotes a new dynamic interaction network and alters RAS conformational dynamics to retain GEF function. These findings reveal a mechanism by which ubiquitination can regulate protein function.Graphical AbstractDisplay OmittedHighlights•Ubiquitination at K104 modulates the conformation and dynamics of Switch II in KRAS•RAS K104 ubiquitination modulates GEF interactions•K104 is a unique site modulating KRAS structure and functionStructural Biology, Biochemistry; Biocomputational Method