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bioRxiv · 10.1101/2023.06.21.545551

Intrinsically disordered regions in the transcription factor MYC:MAX provide DNA selectivity via intramolecular interactions

Schuetz, S.·Bergsdorf, C.·Haenni-Holzinger, S.·Lingel, A.·Renatus, M.·Gossert, A. D.·Jahnke, W.
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Abstract

The basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factor (TF) MYC is in large parts an intrinsically disordered oncoprotein. In complex with its obligate heterodimerization partner MAX, MYC preferentially binds E-Box DNA sequences (CANNTG). At promotors containing these sequence motifs, MYC controls fundamental cellular processes such as cell cycle progression, metabolism, and apoptosis. A vast network of proteins controls MYC function via intermolecular interactions. In this work, we establish another layer of MYC regulation by intramolecular interactions. We use Nuclear Magnetic Resonance (NMR) spectroscopy to identify and map multiple binding sites for the C-terminal MYC:MAX DNA binding domain (DBD) on the intrinsically disordered regions (IDRs) in the MYC N-terminus. We find that these binding events in trans are driven by electrostatic attraction, that they have distinct affinities, and that they are competitive with DNA binding. Thereby, we observe the strongest effects for the N-terminal MYC box 0 (Mb0), a conserved motif involved in MYC transactivation and target gene induction. We prepared recombinant full-length MYC:MAX complex and demonstrate that the interactions identified in this work are also relevant in cis, i.e. as intramolecular interactions. These findings are supported by Surface Plasmon Resonance (SPR) experiments, which revealed that intramolecular IDR:DBD interactions in MYC decelerate the association of MYC:MAX complexes to DNA. Our work offers new insights how bHLH-LZ TFs are regulated by intramolecular interactions, which opens up new possibilities for drug discovery.

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Schuetz, S., Bergsdorf, C., Haenni-Holzinger, S., Lingel, A., Renatus, M., Gossert, A. D., Jahnke, W.. 2023-06-22. Intrinsically disordered regions in the transcription factor MYC:MAX provide DNA selectivity via intramolecular interactions. https://doi.org/10.1101/2023.06.21.545551

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