Structural basis of indisulam-mediated RBM39 recruitment to DCAF15 E3 ligase complex
| Autor: | Mark Knapp, Dan King, Hans Voshol, Fangmin Xu, Ashley Burke, Wei Shu, Rohan Eric John Beckwith, Rajeshri Ganesh Karki, Lili Xie, Viktor Hornak, Joshiawa Paulk, Adarsh Godbole, Jonathan M Solomon, Jennifer Cobb, Christian Wiesmann, Barun Okram, Andreas O. Frank, Celine Be, Patrick Graff, Junping Zhao, Aleem Fazal, Dirksen E. Bussiere, Nathalie Carte, Songchun Jiang, Alexandra Frommlet, Pierre-Yves Michellys, Honnappa Srinivas |
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| Rok vydání: | 2019 |
| Předmět: |
Proteome
Ubiquitin-Protein Ligases Amino Acid Motifs Antineoplastic Agents Plasma protein binding Calorimetry Protein Structure Secondary 03 medical and health sciences Protein structure Ubiquitin Image Processing Computer-Assisted Humans Point Mutation Fluorometry Cloning Molecular RNA Small Interfering Protein Structure Quaternary Molecular Biology 030304 developmental biology chemistry.chemical_classification 0303 health sciences DNA ligase Sulfonamides biology 030302 biochemistry & molecular biology HEK 293 cells Intracellular Signaling Peptides and Proteins Nuclear Proteins RNA-Binding Proteins Cell Biology HCT116 Cells Ubiquitin ligase Cell biology Kinetics HEK293 Cells chemistry RNA splicing biology.protein Degron Peptides Protein Binding |
| Zdroj: | Nature chemical biology. 16(1) |
| ISSN: | 1552-4469 |
| Popis: | The anticancer agent indisulam inhibits cell proliferation by causing degradation of RBM39, an essential mRNA splicing factor. Indisulam promotes an interaction between RBM39 and the DCAF15 E3 ligase substrate receptor, leading to RBM39 ubiquitination and proteasome-mediated degradation. To delineate the precise mechanism by which indisulam mediates the DCAF15-RBM39 interaction, we solved the DCAF15-DDB1-DDA1-indisulam-RBM39(RRM2) complex structure to a resolution of 2.3 A. DCAF15 has a distinct topology that embraces the RBM39(RRM2) domain largely via non-polar interactions, and indisulam binds between DCAF15 and RBM39(RRM2), coordinating additional interactions between the two proteins. Studies with RBM39 point mutants and indisulam analogs validated the structural model and defined the RBM39 α-helical degron motif. The degron is found only in RBM23 and RBM39, and only these proteins were detectably downregulated in indisulam-treated HCT116 cells. This work further explains how indisulam induces RBM39 degradation and defines the challenge of harnessing DCAF15 to degrade additional targets. |
| Databáze: | OpenAIRE |
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