Mitochondrial ClpX activates an essential biosynthetic enzyme through partial unfolding
© 2020, eLife Sciences Publications Ltd. All rights reserved. Mitochondria control the activity, quality, and lifetime of their proteins with an autonomous system of chaperones, but the signals that direct substrate-chaperone interactions and outcomes are poorly understood. We previously discovered...
| Main Authors: | , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications, Ltd
2021
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| Online Access: | https://hdl.handle.net/1721.1/136243 |
| _version_ | 1826212497170890752 |
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| author | Kardon, Julia R Moroco, Jamie A Engen, John R Baker, Tania A |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Kardon, Julia R Moroco, Jamie A Engen, John R Baker, Tania A |
| author_sort | Kardon, Julia R |
| collection | MIT |
| description | © 2020, eLife Sciences Publications Ltd. All rights reserved. Mitochondria control the activity, quality, and lifetime of their proteins with an autonomous system of chaperones, but the signals that direct substrate-chaperone interactions and outcomes are poorly understood. We previously discovered that the mitochondrial AAA+ protein unfoldase ClpX (mtClpX) activates the initiating enzyme for heme biosynthesis, 5-aminolevulinic acid synthase (ALAS), by promoting cofactor incorporation. Here, we ask how mtClpX accomplishes this activation. Using S. cerevisiae proteins, we identified sequence and structural features within ALAS that position mtClpX and provide it with a grip for acting on ALAS. Observation of ALAS undergoing remodeling by mtClpX revealed that unfolding is limited to a region extending from the mtClpX-binding site to the active site. Unfolding along this path is required for mtClpX to gate cofactor binding to ALAS. This targeted unfolding contrasts with the global unfolding canonically executed by ClpX homologs and provides insight into how substrate-chaperone interactions direct the outcome of remodeling. |
| first_indexed | 2024-09-23T15:23:19Z |
| format | Article |
| id | mit-1721.1/136243 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T15:23:19Z |
| publishDate | 2021 |
| publisher | eLife Sciences Publications, Ltd |
| record_format | dspace |
| spelling | mit-1721.1/1362432023-10-06T19:55:01Z Mitochondrial ClpX activates an essential biosynthetic enzyme through partial unfolding Kardon, Julia R Moroco, Jamie A Engen, John R Baker, Tania A Massachusetts Institute of Technology. Department of Biology Howard Hughes Medical Institute © 2020, eLife Sciences Publications Ltd. All rights reserved. Mitochondria control the activity, quality, and lifetime of their proteins with an autonomous system of chaperones, but the signals that direct substrate-chaperone interactions and outcomes are poorly understood. We previously discovered that the mitochondrial AAA+ protein unfoldase ClpX (mtClpX) activates the initiating enzyme for heme biosynthesis, 5-aminolevulinic acid synthase (ALAS), by promoting cofactor incorporation. Here, we ask how mtClpX accomplishes this activation. Using S. cerevisiae proteins, we identified sequence and structural features within ALAS that position mtClpX and provide it with a grip for acting on ALAS. Observation of ALAS undergoing remodeling by mtClpX revealed that unfolding is limited to a region extending from the mtClpX-binding site to the active site. Unfolding along this path is required for mtClpX to gate cofactor binding to ALAS. This targeted unfolding contrasts with the global unfolding canonically executed by ClpX homologs and provides insight into how substrate-chaperone interactions direct the outcome of remodeling. 2021-10-27T20:34:28Z 2021-10-27T20:34:28Z 2020 2021-07-14T12:30:24Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/136243 en 10.7554/ELIFE.54387 eLife Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf eLife Sciences Publications, Ltd eLife |
| spellingShingle | Kardon, Julia R Moroco, Jamie A Engen, John R Baker, Tania A Mitochondrial ClpX activates an essential biosynthetic enzyme through partial unfolding |
| title | Mitochondrial ClpX activates an essential biosynthetic enzyme through partial unfolding |
| title_full | Mitochondrial ClpX activates an essential biosynthetic enzyme through partial unfolding |
| title_fullStr | Mitochondrial ClpX activates an essential biosynthetic enzyme through partial unfolding |
| title_full_unstemmed | Mitochondrial ClpX activates an essential biosynthetic enzyme through partial unfolding |
| title_short | Mitochondrial ClpX activates an essential biosynthetic enzyme through partial unfolding |
| title_sort | mitochondrial clpx activates an essential biosynthetic enzyme through partial unfolding |
| url | https://hdl.handle.net/1721.1/136243 |
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