Physical Sciences and Mathematics Commons^™

Kras Ubiquitination At Lysine 104 Retains Exchange Factor Regulation By Dynamically Modulating The Conformation Of The Interface, Guowei Yin, Jerry Zhang, Vinay Nair, Vinh Truong, Angelo Chaia, Johnny Petela, Joseph S. Harrison, Alemayehu A. Gorfe, Sharon L. Campbell

College of the Pacific Faculty Articles

RAS 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 …