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キーワード:
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要旨:
MutL, a heterodimer of MLH1 and PMS2, plays a central role in human DNA
mismatch repair. It interacts ATP-dependently with the mismatch detector MutS
and assembles and controls further repair enzymes. We tested if the interaction
of MutL with DNA-bound MutS is impaired by cancer-associated mutations in MLH1,
and identified one mutation (Ala128Pro) which abolished interaction as well as
mismatch repair activity. Further examinations revealed three more residues
whose mutation interfered with interaction. Homology modelling of MLH1 showed
that all residues clustered in a small accessible surface patch, suggesting
that the major interaction interface of MutL for MutS is located on the edge of
an extensive ß-sheet that backs the MLH1 ATP binding pocket. Bioinformatic
analysis confirmed that this patch corresponds to a conserved potential protein–
protein interaction interface which is present in both human MLH1 and its
E.coli homologue MutL. MutL could be site-specifically crosslinked to MutS from
this patch, confirming that the bacterial MutL–MutS complex is established by
the corresponding interface in MutL. This is the first study that identifies
the conserved major MutL–MutS interaction interface in MLH1 and demonstrates
that mutations in this interface can affect interaction and mismatch repair,
and thereby can also contribute to cancer development.
