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J. Biol. Chem., Vol. 275, Issue 47, 36550-36555, November 24, 2000
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Is Abolished by a Single Mutation
in the hMSH6 Subunit*
From the Institute of Medical Radiobiology of the University of
Zürich and the Paul Scherrer Institute, August Forel-Strasse
7, Zürich 8008, Switzerland
The most abundant mismatch binding factor in
human cells, hMutS
, is a heterodimer of hMSH2 and hMSH6, two
homologues of the bacterial MutS protein. The C-terminal portions of
all MutS homologues contain an ATP binding motif and are highly
conserved throughout evolution. Although the N termini are generally
divergent, they too contain short conserved sequence elements. A
phenylalanine 
alanine substitution within one such motif,
GXFY(X)5DA, has been shown to
abolish the mismatch binding activity of the MutS protein of
Thermus aquaticus (Malkov, V. A., Biswas, I.,
Camerini-Otero, R. D., and Hsieh, P. (1997) J. Biol.
Chem. 272, 23811-23817). We introduced an identical mutation
into one or both subunits of hMutS. The Phe Ala substitution in
hMSH2 had no effect on the biological activity of the heterodimer. In
contrast, the in vitro mismatch binding and mismatch repair
functions of hMutS were severely attenuated when the hMSH6 subunit
was mutated. Moreover, this variant heterodimer also displayed a
general DNA binding defect. Correspondingly, its ATPase activity could
not be stimulated by either heteroduplex or homoduplex DNA. Thus the
N-terminal portion of hMSH6 appears to impart on hMutS not only the
specificity for recognition and binding of mismatched substrates but
also the ability to bind to homoduplex DNA.
To whom correspondence should be addressed. Tel.: 41-1-634-8910;
Fax: 41-1-634-8904; E-mail: jiricny@imr.unizh.ch.
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