Schuetz, Stefan, Bergsdorf, Christian, Goretzki, Benedikt, Lingel, Andreas, Renatus, Martin, Gossert, Alvar and Jahnke, Wolfgang (2022) The Disordered MAX N-terminus Modulates DNA Binding of the Transcription Factor MYC:MAX. Journal of molecular biology, 434 (22). p. 167833. ISSN 1089-8638

Abstract

The intrinsically disordered protein MYC belongs to the family of basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factors (TFs). In complex with its cognate binding partner MAX, MYC preferentially binds to E-Box promotor sequences where it controls fundamental cellular processes such as cell cycle progression, metabolism, and apoptosis. Intramolecular regulation of MYC:MAX has not yet been investigated in detail. In this work, we use Nuclear Magnetic Resonance (NMR) spectroscopy to identify and map interactions between the disordered MAX N-terminus and the MYC:MAX DNA binding domain (DBD). We find that this binding event is mainly driven by electrostatic interactions and that it is competitive with DNA binding. Using NMR spectroscopy and Surface Plasmon Resonance (SPR), we demonstrate that the MAX N-terminus serves to accelerate DNA binding kinetics of MYC:MAX and MAX:MAX dimers, while it simultaneously provides specificity for E-Box DNA. We also establish that these effects are further enhanced by Casein Kinase 2-mediated phosphorylation of two serine residues in the MAX N-terminus. Our work provides new insights how bHLH-LZ TFs are regulated by intramolecular interactions between disordered regions and the folded DNA binding domain.

Item Type:	Article
Keywords:	Transcription Factors DNA-Binding Proteins Intrinsically Disordered Proteins Casein Kinase II Basic-Leucine Zipper Transcription Factors DNA Serine Proto-Oncogene Proteins c-myc
Date Deposited:	15 Nov 2022 00:45
Last Modified:	15 Nov 2022 00:45
URI:	https://oak.novartis.com/id/eprint/47846