Toxic Activation of an AAA plus Protease by the Antibacterial Drug Cyclomarin A
ATP-driven bacterial AAA+ proteases have been recognized as drug targets. They possess an AAA+ protein (e.g., ClpC), which threads substrate proteins into an associated peptidase (e.g., ClpP). ATPase activity and substrate selection of AAA+ proteins are regulated by adapter proteins that bind to reg...
Saved in:
Published in | Cell chemical biology Vol. 26; no. 8; p. 1169 |
---|---|
Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
15.08.2019
|
Online Access | Get full text |
Cover
Loading…
Abstract | ATP-driven bacterial AAA+ proteases have been recognized as drug targets. They possess an AAA+ protein (e.g., ClpC), which threads substrate proteins into an associated peptidase (e.g., ClpP). ATPase activity and substrate selection of AAA+ proteins are regulated by adapter proteins that bind to regulatory domains, such as the N-terminal domain (NTD). The antibacterial peptide Cyclomarin A (CymA) kills Mycobacterium tuberculosis cells by binding to the NTD of ClpC. How CymA affects ClpC function is unknown. Here, we reveal the mechanism of CymA-induced toxicity. We engineered a CymA-sensitized ClpC chimera and show that CymA activates ATPase and proteolytic activities. CymA mimics adapter binding and enables autonomous protein degradation by ClpC/ClpP with relaxed substrate selectivity. We reconstitute CymA toxicity in E. coli cells expressing engineered ClpC and ClpP, demonstrating that gain of uncontrolled proteolytic activity causes cell death. This validates drug-induced overriding of AAA+ protease activity control as effective antibacterial strategy. |
---|---|
AbstractList | ATP-driven bacterial AAA+ proteases have been recognized as drug targets. They possess an AAA+ protein (e.g., ClpC), which threads substrate proteins into an associated peptidase (e.g., ClpP). ATPase activity and substrate selection of AAA+ proteins are regulated by adapter proteins that bind to regulatory domains, such as the N-terminal domain (NTD). The antibacterial peptide Cyclomarin A (CymA) kills Mycobacterium tuberculosis cells by binding to the NTD of ClpC. How CymA affects ClpC function is unknown. Here, we reveal the mechanism of CymA-induced toxicity. We engineered a CymA-sensitized ClpC chimera and show that CymA activates ATPase and proteolytic activities. CymA mimics adapter binding and enables autonomous protein degradation by ClpC/ClpP with relaxed substrate selectivity. We reconstitute CymA toxicity in E. coli cells expressing engineered ClpC and ClpP, demonstrating that gain of uncontrolled proteolytic activity causes cell death. This validates drug-induced overriding of AAA+ protease activity control as effective antibacterial strategy. |
Author | Franke, Kamila B. Le Breton, Laura Gremer, Sebastian Gloge, Felix Weber-Ban, Eilika Mayer, Matthias P. Mogk, Axel Taylor, Gabrielle Jäger, Jasmin Maurer, Michael Carroni, Marta Bukau, Bernd Linder, Daniela |
Author_xml | – sequence: 1 givenname: Michael surname: Maurer fullname: Maurer, Michael – sequence: 2 givenname: Daniela surname: Linder fullname: Linder, Daniela – sequence: 3 givenname: Kamila B. surname: Franke fullname: Franke, Kamila B. – sequence: 4 givenname: Jasmin surname: Jäger fullname: Jäger, Jasmin – sequence: 5 givenname: Gabrielle surname: Taylor fullname: Taylor, Gabrielle – sequence: 6 givenname: Felix surname: Gloge fullname: Gloge, Felix – sequence: 7 givenname: Sebastian surname: Gremer fullname: Gremer, Sebastian – sequence: 8 givenname: Laura surname: Le Breton fullname: Le Breton, Laura – sequence: 9 givenname: Matthias P. surname: Mayer fullname: Mayer, Matthias P. – sequence: 10 givenname: Eilika surname: Weber-Ban fullname: Weber-Ban, Eilika – sequence: 11 givenname: Marta surname: Carroni fullname: Carroni, Marta organization: Institutionen för biokemi och biofysik – sequence: 12 givenname: Bernd surname: Bukau fullname: Bukau, Bernd – sequence: 13 givenname: Axel surname: Mogk fullname: Mogk, Axel |
BackLink | https://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-173143$$DView record from Swedish Publication Index |
BookMark | eNpNj7FOwzAYhC1UJErpKyA_AAm_7TiOR6uFglSpDIU1so3TukrjKnaAvj1BMDDdDfed7q7RpAudQ-iWQE6AlPeH3O7d0fjQ5hSIzIHnANUFmtKCk0wWvJz881doHuMBYCSZIExM0WYbvrzFyib_oZMPHQ4N1h1WSuFTO0T80ofkdHTYnHHaO6y65I22yfVet3jZDzu8ONs2HHXvR-wGXTa6jW7-pzP0-viwXTxl683qeaHWWSSUpkzLUuoSKqYNFw15N6XhQCuQ1AmoQFMOsimErBoonaAU5E_cjh-4JVZQNkN3v73x050GU596Py4410H7eunfVB36XR2HmghGCsa-AQmNV2Y |
ContentType | Journal Article |
DBID | ABAVF ADTPV AOWAS D8T DG7 ZZAVC |
DOI | 10.1016/j.chembiol.2019.05.008 |
DatabaseName | SWEPUB Stockholms universitet full text SwePub SwePub Articles SWEPUB Freely available online SWEPUB Stockholms universitet SwePub Articles full text |
DatabaseTitleList | |
DeliveryMethod | fulltext_linktorsrc |
Discipline | Anatomy & Physiology |
EISSN | 2451-9456 |
ExternalDocumentID | oai_DiVA_org_su_173143 |
GroupedDBID | 0R~ 0SF 186 457 53G AACTN AAEDT AAEDW AAKRW AALRI AAMRU AAVLU AAXUO ABAVF ABJNI ABMAC ABVKL ACGFS ACIUM ADBBV ADTPV ADVLN AFTJW AITUG AKAPO AKRWK ALMA_UNASSIGNED_HOLDINGS AMRAJ AOWAS D8T DG7 EBS EJD FCP FDB FIRID HH5 JIG KOO M41 NCXOZ O9- OK1 RCE RIG ROL SSZ ZZAVC |
ID | FETCH-LOGICAL-s122t-a969a6083ab57f1db6b5028092e7080a2509f4798f06e722099a60c9455c1c723 |
ISSN | 2451-9456 2451-9448 |
IngestDate | Tue Oct 01 22:28:02 EDT 2024 |
IsDoiOpenAccess | true |
IsOpenAccess | true |
IsPeerReviewed | true |
IsScholarly | true |
Issue | 8 |
Language | English |
LinkModel | OpenURL |
MergedId | FETCHMERGED-LOGICAL-s122t-a969a6083ab57f1db6b5028092e7080a2509f4798f06e722099a60c9455c1c723 |
OpenAccessLink | https://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-173143 |
ParticipantIDs | swepub_primary_oai_DiVA_org_su_173143 |
PublicationCentury | 2000 |
PublicationDate | 2019-08-15 |
PublicationDateYYYYMMDD | 2019-08-15 |
PublicationDate_xml | – month: 08 year: 2019 text: 2019-08-15 day: 15 |
PublicationDecade | 2010 |
PublicationTitle | Cell chemical biology |
PublicationYear | 2019 |
SSID | ssj0001637137 |
Score | 2.4965582 |
Snippet | ATP-driven bacterial AAA+ proteases have been recognized as drug targets. They possess an AAA+ protein (e.g., ClpC), which threads substrate proteins into an... |
SourceID | swepub |
SourceType | Open Access Repository |
StartPage | 1169 |
Title | Toxic Activation of an AAA plus Protease by the Antibacterial Drug Cyclomarin A |
URI | https://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-173143 |
Volume | 26 |
hasFullText | 1 |
inHoldings | 1 |
isFullTextHit | |
isPrint | |
link | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnV3Pb9MwFLbKuHBBYwMBA-QDcIlc1YntxMcwmKYd4LKh3SLbjauiNpnaRKL89Tz_aNNBD4NLFFn5_T69PD-_73sIvQefKKllBRGFZYQJlRGpKSdaC2Gsyfg0VPl-FZc37OqW345Gdq9qqe_02Pw6yCv5H6vCGNjVsWT_wbK7i8IA7IN9YQsWhu3DbNz-nJukNNsWZX5Rv0nKskzuFv3asQA6t_ziY0xHIWm6uQ7yzM7brfpZcr4xi3YJE-YmZjW3qgUup2e2agJRqmlIX_exC_Z-1b0r63Hii6uBur7z-b43fB3KN5bzhUo-jXe1O36tns3CeVdqvYxi4DEX4ehPBQlszOCyUsYpkYxHcesDY9HnBpZ8xFax50ApDZ1b_vLsIcnwY-ze3L20q8qTXnR1Ugz_snuq2Z_n38uqXc2qdV_RPIPI8BF67AQTmXfgfMjFiSwP8qrxYX3Ttd2D7xHLD9__D5lZH5pcH6OncU6BywCQZ2hUNyfotGxU1y43-CP2Vb7egKfom8cMHjCDW4tVgwEz2GEGbzGD9QYDZvA9zGCHGTxgBpfP0c3Fl-vzSxKbapA1TdOOKCmkEhB4K81zS6daaO6W12Va5zB7UBASS8tyWdiJqPPUMavhcAPfgRtq8jR7gY6atqlfIix0qiWEqIZlU2YzJtWkqKfGpIYqmAnQV-hD-CzVXVBOqQ5b5fUDjztDTwbQvUFH3aqv30JI2Ol33p6_AX2UXjw |
link.rule.ids | 230,314,780,784,885,27924,27925 |
linkProvider | ABC ChemistRy |
openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Toxic+Activation+of+an+AAA+plus+Protease+by+the+Antibacterial+Drug+Cyclomarin+A&rft.jtitle=Cell+chemical+biology&rft.au=Maurer%2C+Michael&rft.au=Linder%2C+Daniela&rft.au=Franke%2C+Kamila+B.&rft.au=J%C3%A4ger%2C+Jasmin&rft.date=2019-08-15&rft.issn=2451-9456&rft.eissn=2451-9456&rft.volume=26&rft.issue=8&rft.spage=1169&rft_id=info:doi/10.1016%2Fj.chembiol.2019.05.008&rft.externalDocID=oai_DiVA_org_su_173143 |
thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=2451-9456&client=summon |
thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=2451-9456&client=summon |
thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=2451-9456&client=summon |