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Papers In Press, published online ahead of print August 10, 2000
Institute of Medical Radiobiology, Zurich 8008
Corresponding Author: jiricny{at}imr.unizh.ch
The most abundant mismatch binding factor in human cells, hMutS
J. Biol. Chem, 10.1074/jbc.M005987200
Submitted on July 7, 2000
Revised on August 9, 2000
Accepted on August 10, 2000
Mismatch recognition and DNA-dependent stimulation of the ATPase activity of hMutS
are abolished by a F432A mutation in the hMSH6 subunit
, 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 {forward arrow} 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 et al., J. Biol. Chem. 272, 23811-23817 (1997)]. We introduced an identical mutation into one or both subunits of hMutS. The F{forward arrow}A 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 displayed also a general DNA binding defect. Correspondingly, its ATPase activity could be stimulated neither by heteroduplex nor by homoduplex DNA. The N-terminal portion of hMSH6 thus 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.
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