Structural basis for RKIP binding with its substrate Raf1 kinase |
| |
Authors: | Zhihua Wu Cuiping Fu Lina Shi Lu Ruan Donghai Lin Chenyun Guo |
| |
Institution: | 1. Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, 422 Siming South Road, Xiamen, 361005, Fujian, China
|
| |
Abstract: | Raf1 kinase inhibitor protein (RKIP) negatively regulates the Raf1/MEK/ERK pathway which is vital for cell growth and differentiation. It is also a biomarker in clinical cancer diagnosis. RKIP binds to the N-terminus of Raf1 kinase but little is known about the structural basis of RKIP binding with Raf1. Here, we demonstrate that the N-terminus of human Raf1 kinase (hRaf11-147aa) binds with human RKIP (hRKIP) at its ligand-binding pocket, loop “127–149”, and the C-terminal helix by NMR experiments. D70, D72, E83, Y120, and Y181 were further verified as the key residues participating in the interaction of hRKIP and hRaf11-147aa. G143-R146 fragment was also critical for hRKIP binding with hRaf11-147aa, for its deletion decreased the binding affinity around 300 times, from 154 to 0.46 mM?1. Our results provide important structural clues for designing the lead compound that disrupts RKIP–Raf1 interaction. |
| |
Keywords: | |
本文献已被 SpringerLink 等数据库收录! |
|