Crystal structure of Mycobacterium tuberculosis ClpP1P2 suggests a model for peptidase activation by AAA+ partner binding and substrate delivery
Caseinolytic peptidase P (ClpP), a double-ring peptidase with 14 subunits, collaborates with ATPases associated with diverse activities (AAA+) partners to execute ATP-dependent protein degradation. Although many ClpP enzymes self-assemble into catalytically active homo-tetradecamers able to cleave s...
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2015
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| Online Access: | http://hdl.handle.net/1721.1/96354 https://orcid.org/0000-0002-9309-8662 https://orcid.org/0000-0002-1719-5399 |
| _version_ | 1826217990659506176 |
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| author | Schmitz, Karl R. Carney, Daniel W. Sello, Jason K. Sauer, Robert T |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Schmitz, Karl R. Carney, Daniel W. Sello, Jason K. Sauer, Robert T |
| author_sort | Schmitz, Karl R. |
| collection | MIT |
| description | Caseinolytic peptidase P (ClpP), a double-ring peptidase with 14 subunits, collaborates with ATPases associated with diverse activities (AAA+) partners to execute ATP-dependent protein degradation. Although many ClpP enzymes self-assemble into catalytically active homo-tetradecamers able to cleave small peptides, the Mycobacterium tuberculosis enzyme consists of discrete ClpP1 and ClpP2 heptamers that require a AAA+ partner and protein–substrate delivery or a peptide agonist to stabilize assembly of the active tetradecamer. Here, we show that cyclic acyldepsipeptides (ADEPs) and agonist peptides synergistically activate ClpP1P2 by mimicking AAA + partners and substrates, respectively, and determine the structure of the activated complex. Our studies establish the basis of heteromeric ClpP1P2 assembly and function, reveal tight coupling between the conformations of each ring, show that ADEPs bind only to one ring but appear to open the axial pores of both rings, provide a foundation for rational drug development, and suggest strategies for studying the roles of individual ClpP1 and ClpP2 rings in Clp-family proteolysis |
| first_indexed | 2024-09-23T17:12:24Z |
| format | Article |
| id | mit-1721.1/96354 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T17:12:24Z |
| publishDate | 2015 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/963542022-10-03T11:06:14Z Crystal structure of Mycobacterium tuberculosis ClpP1P2 suggests a model for peptidase activation by AAA+ partner binding and substrate delivery Schmitz, Karl R. Carney, Daniel W. Sello, Jason K. Sauer, Robert T Massachusetts Institute of Technology. Department of Biology Schmitz, Karl R. Sauer, Robert T. Caseinolytic peptidase P (ClpP), a double-ring peptidase with 14 subunits, collaborates with ATPases associated with diverse activities (AAA+) partners to execute ATP-dependent protein degradation. Although many ClpP enzymes self-assemble into catalytically active homo-tetradecamers able to cleave small peptides, the Mycobacterium tuberculosis enzyme consists of discrete ClpP1 and ClpP2 heptamers that require a AAA+ partner and protein–substrate delivery or a peptide agonist to stabilize assembly of the active tetradecamer. Here, we show that cyclic acyldepsipeptides (ADEPs) and agonist peptides synergistically activate ClpP1P2 by mimicking AAA + partners and substrates, respectively, and determine the structure of the activated complex. Our studies establish the basis of heteromeric ClpP1P2 assembly and function, reveal tight coupling between the conformations of each ring, show that ADEPs bind only to one ring but appear to open the axial pores of both rings, provide a foundation for rational drug development, and suggest strategies for studying the roles of individual ClpP1 and ClpP2 rings in Clp-family proteolysis National Institutes of Health (U.S.) (NIH Grant GM-101988) Brown University National Science Foundation (U.S.) (CAREER award) National Institute of General Medical Sciences (U.S.) (Grant P41 GM103403) United States. Dept. of Energy (Contract DE-AC02-06CH11357) 2015-04-02T19:01:24Z 2015-04-02T19:01:24Z 2014-09 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/96354 Schmitz, K. R., D. W. Carney, J. K. Sello, and R. T. Sauer. “Crystal Structure of Mycobacterium Tuberculosis ClpP1P2 Suggests a Model for Peptidase Activation by AAA+ Partner Binding and Substrate Delivery.” Proceedings of the National Academy of Sciences 111, no. 43 (September 29, 2014): E4587–E4595. https://orcid.org/0000-0002-9309-8662 https://orcid.org/0000-0002-1719-5399 en_US http://dx.doi.org/10.1073/pnas.1417120111 Proceedings of the National Academy of Sciences 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 National Academy of Sciences (U.S.) National Academy of Sciences (U.S.) |
| spellingShingle | Schmitz, Karl R. Carney, Daniel W. Sello, Jason K. Sauer, Robert T Crystal structure of Mycobacterium tuberculosis ClpP1P2 suggests a model for peptidase activation by AAA+ partner binding and substrate delivery |
| title | Crystal structure of Mycobacterium tuberculosis ClpP1P2 suggests a model for peptidase activation by AAA+ partner binding and substrate delivery |
| title_full | Crystal structure of Mycobacterium tuberculosis ClpP1P2 suggests a model for peptidase activation by AAA+ partner binding and substrate delivery |
| title_fullStr | Crystal structure of Mycobacterium tuberculosis ClpP1P2 suggests a model for peptidase activation by AAA+ partner binding and substrate delivery |
| title_full_unstemmed | Crystal structure of Mycobacterium tuberculosis ClpP1P2 suggests a model for peptidase activation by AAA+ partner binding and substrate delivery |
| title_short | Crystal structure of Mycobacterium tuberculosis ClpP1P2 suggests a model for peptidase activation by AAA+ partner binding and substrate delivery |
| title_sort | crystal structure of mycobacterium tuberculosis clpp1p2 suggests a model for peptidase activation by aaa partner binding and substrate delivery |
| url | http://hdl.handle.net/1721.1/96354 https://orcid.org/0000-0002-9309-8662 https://orcid.org/0000-0002-1719-5399 |
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