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J. Biol. Chem., Vol. 276, Issue 15, 12113-12119, April 13, 2001
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From the Department of Pharmacology and Molecular Toxicology,
University of Massachusetts Medical School, Worcester,
Massachusetts 01655
Site-directed mutagenesis was performed on
several areas of MutH based on the similarity of MutH and
PvuII structural models. The aims were to identify
DNA-binding residues; to determine whether MutH has the same mechanism
for DNA binding and catalysis as PvuII; and to localize the
residues responsible for MutH stimulation by MutL. No DNA-binding
residues were identified in the two flexible loop regions of MutH,
although similar loops in PvuII are involved in DNA
binding. Two histidines in MutH are in a similar position as two
histidines (His-84 and His-85) in PvuII that signal
for DNA binding and catalysis. These MutH histidines (His-112 and His-115) were changed to alanines, but the mutant proteins had wild-type activity both in vivo and in vitro.
The results indicate that the MutH signal for DNA binding and catalysis
remains unknown. Instead, a lysine residue (Lys-48) was found in the
first flexible loop that functions in catalysis together with the three
presumed catalytic amino acids (Asp-70, Glu-77, and Lys-79). Two
deletion mutations (MutH
224 and MutH214) in the C-terminal end of
the protein, localized the MutL stimulation region to five amino acids (Ala-220, Leu-221, Leu-222, Ala-223, and Arg-224).
To whom correspondence should be addressed: Dept. of Pharmacology
and Molecular Toxicology, University of Massachusetts Medical School,
55 Lake Ave. North, Worcester, MA 01655. Tel.: 508-856-3330; Fax:
508-856-5080; E-mail: martin.marinus@umassmed.edu.
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