Mechanistic insights into the phosphorylation-regulated a disordered protein interaction module

Area of Science:

• Molecular Biology
• Biochemistry
• Structural Biology

Background:

• The TFIIS N-terminal domain (TND) is a key protein scaffold recognizing TND-interacting motifs (TIMs).
• Understanding TND-TIM interactions is vital for the transcription machinery.
• Disordered protein interactions are crucial in cellular processes.

Purpose of the Study:

• Investigate the conformational ensembles of the TND-TIM interaction module.
• Elucidate the role of phosphorylation in regulating TND-TIM interactions.
• Provide atomic-level insights into phosphorylation-regulated TND-TIM interactions.

Main Methods:

• Molecular dynamics simulations were employed to study TND-TIM complexes.
• Simulations analyzed conformational stability and dynamics.
• Experimental structures were used as starting points for simulations.

Main Results:

• Experimental TND-TIM complexes (P75-PogZ, P75-IWS1) showed stable conformations in simulations.
• Unstable complexes (P75-ASK, HRP2-IWS1) exhibited shifts in TIM helix-1.
• Phosphorylation significantly enhanced TND-TIM interactions and complex stability.

Conclusions:

• Phosphorylation stabilizes TND-TIM complexes through specific hydrogen bonds and enhanced residue interactions.
• A general rule for phosphorylation-mediated regulation of TND-TIM interactions was identified.
• This study deepens the understanding of protein interactome assembly in transcription.