Conformational change in MSH2-MSH6 upon binding DNA coupled to ATPase activity

Area of Science:

• Molecular Biology
• Biochemistry
• Structural Biology

Background:

• Postreplication DNA mismatch repair is crucial for genomic stability.
• Eukaryotic MSH2-MSH6 and prokaryotic MutS initiate DNA mismatch repair with conserved structures.
• Crystal structures show MSH2-MSH6 and MutS bound to DNA in a closed conformation.

Purpose of the Study:

• To investigate the conformational dynamics of human MSH2-MSH6 in the absence of DNA.
• To understand the relationship between DNA binding and ATPase activity in MSH2-MSH6.

Main Methods:

• Long molecular dynamics simulations of human MSH2-MSH6.
• Analysis of protein conformation changes and domain movements.

Main Results:

• In the absence of DNA, MSH2-MSH6 adopts an altered conformation.
• The clamp and lever domains of MSH2 and MSH6 open dramatically and asymmetrically.
• This opening is coupled to changes in ATPase domains, explaining reduced ATPase activity in DNA-free states.

Conclusions:

• The study reveals the dynamic nature of MSH2-MSH6 outside of DNA binding.
• Conformational changes in clamp and lever domains are linked to ATPase activity.
• This provides insight into the allosteric regulation of DNA mismatch repair initiation.