Structure of the Endonuclease Domain of MutL: Unlicensed to Cut
DNA mismatch repair corrects errors that have escaped polymerase proofreading, increasing replication fidelity 100- to 1000-fold in organisms ranging from bacteria to humans. The MutL protein plays a central role in mismatch repair by coordinating multiple protein-protein interactions that signal st...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
| Published: |
Elsevier B.V.
2015
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| Online Access: | http://hdl.handle.net/1721.1/96088 https://orcid.org/0000-0001-7243-8261 |
| _version_ | 1826207558282510336 |
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| author | Pillon, Monica C. Lorenowicz, Jessica J. Uckelmann, Michael Klocko, Andrew D. Mitchell, Ryan R. Chung, Yu Seon Modrich, Paul Walker, Graham C. Simmons, Lyle A. Friedhoff, Peter Guarne, Alba |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Pillon, Monica C. Lorenowicz, Jessica J. Uckelmann, Michael Klocko, Andrew D. Mitchell, Ryan R. Chung, Yu Seon Modrich, Paul Walker, Graham C. Simmons, Lyle A. Friedhoff, Peter Guarne, Alba |
| author_sort | Pillon, Monica C. |
| collection | MIT |
| description | DNA mismatch repair corrects errors that have escaped polymerase proofreading, increasing replication fidelity 100- to 1000-fold in organisms ranging from bacteria to humans. The MutL protein plays a central role in mismatch repair by coordinating multiple protein-protein interactions that signal strand removal upon mismatch recognition by MutS. Here we report the crystal structure of the endonuclease domain of Bacillus subtilis MutL. The structure is organized in dimerization and regulatory subdomains connected by a helical lever spanning the conserved endonuclease motif. Additional conserved motifs cluster around the lever and define a Zn2+-binding site that is critical for MutL function in vivo. The structure unveils a powerful inhibitory mechanism to prevent undesired nicking of newly replicated DNA and allows us to propose a model describing how the interaction with MutS and the processivity clamp could license the endonuclease activity of MutL. The structure also provides a molecular framework to propose and test additional roles of MutL in mismatch repair. |
| first_indexed | 2024-09-23T13:51:25Z |
| format | Article |
| id | mit-1721.1/96088 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:51:25Z |
| publishDate | 2015 |
| publisher | Elsevier B.V. |
| record_format | dspace |
| spelling | mit-1721.1/960882022-09-28T16:38:16Z Structure of the Endonuclease Domain of MutL: Unlicensed to Cut Pillon, Monica C. Lorenowicz, Jessica J. Uckelmann, Michael Klocko, Andrew D. Mitchell, Ryan R. Chung, Yu Seon Modrich, Paul Walker, Graham C. Simmons, Lyle A. Friedhoff, Peter Guarne, Alba Massachusetts Institute of Technology. Department of Biology Walker, Graham C. DNA mismatch repair corrects errors that have escaped polymerase proofreading, increasing replication fidelity 100- to 1000-fold in organisms ranging from bacteria to humans. The MutL protein plays a central role in mismatch repair by coordinating multiple protein-protein interactions that signal strand removal upon mismatch recognition by MutS. Here we report the crystal structure of the endonuclease domain of Bacillus subtilis MutL. The structure is organized in dimerization and regulatory subdomains connected by a helical lever spanning the conserved endonuclease motif. Additional conserved motifs cluster around the lever and define a Zn2+-binding site that is critical for MutL function in vivo. The structure unveils a powerful inhibitory mechanism to prevent undesired nicking of newly replicated DNA and allows us to propose a model describing how the interaction with MutS and the processivity clamp could license the endonuclease activity of MutL. The structure also provides a molecular framework to propose and test additional roles of MutL in mismatch repair. American Cancer Society (Research Professor) Natural Sciences and Engineering Research Council of Canada (NSERC scholarship) National Institutes of Health (U.S.) (CA21615) National Institutes of Health (U.S.) (GM45190) Natural Sciences and Engineering Research Council of Canada (NSERC, 288295) Deutsche Forschungsgemeinschaft (FR-1495/4-1) University of Michigan (Start-up funds) 2015-03-19T18:51:03Z 2015-03-19T18:51:03Z 2010-07 2010-04 Article http://purl.org/eprint/type/JournalArticle 10972765 http://hdl.handle.net/1721.1/96088 Pillon, Monica C., Jessica J. Lorenowicz, Michael Uckelmann, Andrew D. Klocko, Ryan R. Mitchell, Yu Seon Chung, Paul Modrich, et al. “Structure of the Endonuclease Domain of MutL: Unlicensed to Cut.” Molecular Cell 39, no. 1 (July 2010): 145–151. © 2010 Elsevier Inc. https://orcid.org/0000-0001-7243-8261 en_US http://dx.doi.org/10.1016/j.molcel.2010.06.027 Molecular Cell Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Elsevier B.V. Elsevier |
| spellingShingle | Pillon, Monica C. Lorenowicz, Jessica J. Uckelmann, Michael Klocko, Andrew D. Mitchell, Ryan R. Chung, Yu Seon Modrich, Paul Walker, Graham C. Simmons, Lyle A. Friedhoff, Peter Guarne, Alba Structure of the Endonuclease Domain of MutL: Unlicensed to Cut |
| title | Structure of the Endonuclease Domain of MutL: Unlicensed to Cut |
| title_full | Structure of the Endonuclease Domain of MutL: Unlicensed to Cut |
| title_fullStr | Structure of the Endonuclease Domain of MutL: Unlicensed to Cut |
| title_full_unstemmed | Structure of the Endonuclease Domain of MutL: Unlicensed to Cut |
| title_short | Structure of the Endonuclease Domain of MutL: Unlicensed to Cut |
| title_sort | structure of the endonuclease domain of mutl unlicensed to cut |
| url | http://hdl.handle.net/1721.1/96088 https://orcid.org/0000-0001-7243-8261 |
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