Transformation of MutL by ATP binding and hydrolysis: a switch in DNA mismatch repair

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• The MutL protein is crucial for DNA mismatch repair and possesses ATPase activity.
• MutL belongs to an ATPase superfamily including DNA topoisomerase II and Hsp90.

Purpose of the Study:

• To elucidate the structural basis of E. coli MutL's ATPase activity.
• To understand the mechanism of ATP hydrolysis and its regulation by DNA.

Main Methods:

• X-ray crystallography was used to determine the structures of an E. coli MutL ATPase fragment (LN40) bound to ADPnP and ADP.
• Analysis of structural changes upon nucleotide binding and hydrolysis.

Main Results:

• The crystal structures revealed ordered residues upon nucleotide binding, facilitating ADPnP binding and LN40 dimerization.
• ATP hydrolysis triggers the release of key loops and dissociation of the LN40 dimer.
• Dimerization of LN40 is essential and rate-limiting for ATP hydrolysis.

Conclusions:

• MutL dimerization is a critical step in its ATPase cycle.
• DNA stimulation of MutL's ATPase activity suggests a regulatory switch mechanism for DNA mismatch repair coordination.