Dynamic action of an intrinsically disordered protein in DNA compaction that induces mycobacterial dormancy

Area of Science:

• Microbiology
• Molecular Biology
• Structural Biology

Background:

• Mycobacteria are significant human pathogens capable of entering a dormant, persistent state.
• Mycobacterial DNA-binding protein 1 (MDP1) is a histone-like protein crucial for inducing dormancy phenotypes like chromosome compaction and growth suppression.
• The intrinsically disordered region (IDR) of MDP1 is essential for its function but poses challenges in mechanistic studies.

Purpose of the Study:

• To elucidate the molecular and structural mechanisms by which MDP1 compacts DNA.
• To understand how MDP1's IDR mediates DNA binding and influences mycobacterial dormancy.

Main Methods:

• High-speed atomic force microscopy (HS-AFM) to visualize MDP1-DNA interactions.
• Coarse-grained molecular dynamics (CG-MD) simulations to model DNA cross-linking.
• Investigating the role of MDP1's intrinsically disordered region (IDR).

Main Results:

• Monomeric MDP1 was observed to bundle adjacent DNA duplexes side-by-side through its IDR.
• A novel dynamic DNA cross-linking model was revealed, where the stretched IDR acts like double-sided tape.
• MDP1's IDR hijacks HU function, leading to significant mycobacterial growth arrest.

Conclusions:

• MDP1 utilizes its IDR for reversible DNA cross-linking, a mechanism essential for inducing dormancy.
• This IDR-mediated DNA cross-linking provides a model for how MDP1 suppresses genomic function in dormant, non-replicating mycobacteria.
• The findings offer insights into the survival strategies of persistent mycobacteria.