Mechanism of formation of a toroid around DNA by the mismatch sensor protein

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• The DNA mismatch repair (MMR) pathway corrects errors during DNA replication.
• MutS is the key protein that senses DNA mismatches.
• Previous understanding lacked clarity on how MutS loads DNA and generates force for DNA bending.

Purpose of the Study:

• To elucidate the mechanism of DNA loading into the MutS central tunnel.
• To identify the source of force responsible for DNA bending by MutS.
• To understand the allosteric regulation of adenosine triphosphate (ATP) expulsion in MutS.

Main Methods:

• Structural analysis of MutS dimers with and without DNA.
• Comparative structural studies of MutS-DNA complexes.
• Mechanistic modeling of DNA bending and toroid formation.

Main Results:

• MutS forms a symmetric dimer with a central gap for DNA entry in the absence of DNA.
• DNA binding induces a significant conformational change, with one monomer (Bm) moving ~50 Å.
• The N-terminal domains of MutS press on DNA, bending it like pliers; Bm's movement is the primary force generator.
• An allosteric mechanism governing ATP expulsion from the Am monomer upon DNA binding was identified.

Conclusions:

• The study provides a mechanistic model for MutS-DNA complex assembly, the initial step in MMR.
• MutS utilizes a 'pliers-like' mechanism, driven by monomer movement, to load and bend DNA.
• Insights into ATP-dependent allostery in MutS function were gained, enhancing understanding of MMR initiation.