SH003 - Disordered tails tune DNA binding and specificity in transcription factor Myc:Max

SH003

Disordered tails tune DNA binding and specificity in transcription factor Myc:Max

S. Peer^1,*, Y. Levy¹

¹Weizmann Institute of Science, Rehovoth, Israel

 

Rationale: Transcription factors must rapidly locate rare cognate sites within genomes dominated by near-cognate sequences. Although intrinsically disordered regions (IDRs) are widespread in transcription factors, the frequent presence of negatively charged tails presents a biophysical paradox and their functional role in DNA target search remains poorly understood.

Methods: We used coarse-grained molecular dynamics simulations to investigate how acidic terminal tails in the Myc:Max bHLH-LZ transcription factor complex influence DNA-binding kinetics, diffusion modes, and target specificity, including the effects of phosphorylation and inter-tail electrostatic interactions.

Results: Negatively charged tails reshape the DNA search process by shifting motion along DNA from sliding to faster hopping, thereby accelerating target localization. This acceleration is driven by a dynamic autoinhibitory mechanism: the negative tails transiently compete with DNA for interactions with the positively charged DNA-binding domain. Crucially, this dynamic screening increases specificity and functions as a kinetic filter, preserving high affinity for cognate sites while drastically reducing dwell time on decoy sequences. We further show that while phosphorylation amplifies this acceleration, it imposes a trade-off by destabilizing target binding, suggesting the charge density is evolutionarily optimized. Finally, we reveal that attractive electrostatic interactions between the Myc and Max tails in the heterodimer partially attenuate this acceleration, adding a layer of regulation.

Conclusions: Negative disordered tails emerge as active modulators of transcription factor DNA targeting, operating through electrostatic competition to tune search dynamics and binding fidelity. This mechanism provides a kinetic framework for balancing rapid genome exploration with precise target recognition, advancing our understanding of transcriptional regulation.

Disclosure of Interest: None declared