Structural basis of indisulam-mediated RBM39 recruitment to DCAF15 E3 ligase complex

Area of Science:

• Molecular Biology
• Structural Biology
• Cancer Therapeutics

Background:

• Indisulam is an anticancer agent that inhibits cell proliferation by targeting the mRNA splicing factor RBM39.
• Indisulam induces RBM39 degradation through its interaction with the DCAF15 E3 ligase substrate receptor, leading to ubiquitination and proteasomal degradation.

Purpose of the Study:

• To elucidate the precise molecular mechanism by which indisulam mediates the interaction between DCAF15 and RBM39.
• To determine the structural basis for indisulam-induced RBM39 degradation.

Main Methods:

• X-ray crystallography was used to solve the structure of the DCAF15-DDB1-DDA1-indisulam-RBM39(RRM2) complex.
• Site-directed mutagenesis of RBM39 and analysis of indisulam analogs were employed to validate the structural model.

Main Results:

• The crystal structure revealed that DCAF15 interacts with the RBM39(RRM2) domain via non-polar interactions.
• Indisulam acts as a molecular bridge, binding between DCAF15 and RBM39(RRM2) and stabilizing their interaction.
• A specific RBM39 α-helical degron motif was identified, crucial for DCAF15 recognition and degradation. This motif is present only in RBM23 and RBM39.

Conclusions:

• This study provides a detailed structural understanding of how indisulam induces RBM39 degradation.
• The findings highlight the specificity of the DCAF15-RBM39 interaction mediated by indisulam and the identified degron motif.
• The results present a challenge and opportunity for developing novel therapeutics that harness DCAF15 to degrade other target proteins.