The GHKL ATPase Family as a Paradigm for MutL Homolog Function in DNA Mismatch Repair

ATP hydrolysis drives essential processes across biology, from nucleic acid translocation and conformational switching to signal transduction. The GHKL ATPase family-DNA Gyrase B, Heat Shock Protein 90 (Hsp90), Histidine Kinases, and MutL homologs-shares a Bergerat-fold that couples nucleotide binding and hydrolysis to conformational changes, dimerization, and signaling. Despite their diverse roles, GHKL proteins rely on common ATP-dependent principles. Within this family, MutLα (MLH1-PMS2 in humans, Mlh1-Pms1 in yeast) is central to eukaryotic mismatch repair, where it provides the endonuclease activity needed for strand incision and coordinates interactions with other repair partners. MutLα exemplifies how the Bergerat-fold has been adapted to regulate DNA interactions, partner communication, and protein turnover on DNA. By examining MutLα through the lens of other GHKL proteins, we can clarify how ATP binding and hydrolysis drive its conformational dynamics, nuclease activation, and regulation within its pathway, highlighting how conserved mechanistic strategies are repurposed across biological systems.