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Molecular and Cellular Biology, September 2000, p. 6390-6398, Vol. 20, No. 17
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Functional Studies on the Candidate ATPase Domains of Saccharomyces cerevisiae MutLalpha

Phuoc T. Tran and R. Michael Liskay*

Department of Molecular and Medical Genetics, Oregon Health Sciences University, Portland, Oregon 97201

Received 21 March 2000/Returned for modification 4 May 2000/Accepted 7 June 2000

Saccharomyces cerevisiae MutL homologues Mlh1p and Pms1p form a heterodimer, termed MutLalpha , that is required for DNA mismatch repair after mismatch binding by MutS homologues. Recent sequence and structural studies have placed the NH2 termini of MutL homologues in a new family of ATPases. To address the functional significance of this putative ATPase activity in MutLalpha , we mutated conserved motifs for ATP hydrolysis and ATP binding in both Mlh1p and Pms1p and found that these changes disrupted DNA mismatch repair in vivo. Limited proteolysis with purified recombinant MutLalpha demonstrated that the NH2 terminus of MutLalpha undergoes conformational changes in the presence of ATP and nonhydrolyzable ATP analogs. Furthermore, two-hybrid analysis suggested that these ATP-binding-induced conformational changes promote an interaction between the NH2 termini of Mlh1p and Pms1p. Surprisingly, analysis of specific mutants suggested differential requirements for the ATPase motifs of Mlh1p and Pms1p during DNA mismatch repair. Taken together, these results suggest that MutLalpha undergoes ATP-dependent conformational changes that may serve to coordinate downstream events during yeast DNA mismatch repair.

* Corresponding author. Mailing address: Department of Molecular and Medical Genetics, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd., L103, Portland, OR 97201-3098. Phone: (503) 494-3475. Fax: (503) 494-6886. E-mail: liskaym{at}ohsu.edu.

Molecular and Cellular Biology, September 2000, p. 6390-6398, Vol. 20, No. 17
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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