Cooperative Domain Formation by Homologous Motifs in HOIL-1L and SHARPIN Plays A Crucial Role in LUBAC Stabilization
Summary: The linear ubiquitin chain assembly complex (LUBAC) participates in inflammatory and oncogenic signaling by conjugating linear ubiquitin chains to target proteins. LUBAC consists of the catalytic HOIP subunit and two accessory subunits, HOIL-1L and SHARPIN. Interactions between the ubiquiti...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2018-04-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124718304881 |
| _version_ | 1818482163976241152 |
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| author | Hiroaki Fujita Akira Tokunaga Satoshi Shimizu Amanda L. Whiting Francisco Aguilar-Alonso Kenji Takagi Erik Walinda Yoshiteru Sasaki Taketo Shimokawa Tsunehiro Mizushima Izuru Ohki Mariko Ariyoshi Hidehito Tochio Federico Bernal Masahiro Shirakawa Kazuhiro Iwai |
| author_facet | Hiroaki Fujita Akira Tokunaga Satoshi Shimizu Amanda L. Whiting Francisco Aguilar-Alonso Kenji Takagi Erik Walinda Yoshiteru Sasaki Taketo Shimokawa Tsunehiro Mizushima Izuru Ohki Mariko Ariyoshi Hidehito Tochio Federico Bernal Masahiro Shirakawa Kazuhiro Iwai |
| author_sort | Hiroaki Fujita |
| collection | DOAJ |
| description | Summary: The linear ubiquitin chain assembly complex (LUBAC) participates in inflammatory and oncogenic signaling by conjugating linear ubiquitin chains to target proteins. LUBAC consists of the catalytic HOIP subunit and two accessory subunits, HOIL-1L and SHARPIN. Interactions between the ubiquitin-associated (UBA) domains of HOIP and the ubiquitin-like (UBL) domains of two accessory subunits are involved in LUBAC stabilization, but the precise molecular mechanisms underlying the formation of stable trimeric LUBAC remain elusive. We solved the co-crystal structure of the binding regions of the trimeric LUBAC complex and found that LUBAC-tethering motifs (LTMs) located N terminally to the UBL domains of HOIL-1L and SHARPIN heterodimerize and fold into a single globular domain. This interaction is resistant to dissociation and plays a critical role in stabilizing trimeric LUBAC. Inhibition of LTM-mediated HOIL-1L/SHARPIN dimerization profoundly attenuated the function of LUBAC, suggesting LTM as a superior target of LUBAC destabilization for anticancer therapeutics. : Fujita et al. report a crystal structure of the trimeric LUBAC core and show that motifs in HOIL-1L and SHARPIN fold into a single domain critical for LUBAC stabilization. The authors also develop an inhibitor of this interaction that destabilizes LUBAC and kills cancer cells. Keywords: linear ubiquitin chains, LUBAC, LUBAC-tethering motif, HOIP, HOIL-1L, SHARPIN, ubiquitin-like domain, ubiquitin-associated domain, cancer |
| first_indexed | 2024-12-10T11:44:34Z |
| format | Article |
| id | doaj.art-7c862e83f5e5418699f786a096c66df4 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-10T11:44:34Z |
| publishDate | 2018-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-7c862e83f5e5418699f786a096c66df42022-12-22T01:50:08ZengElsevierCell Reports2211-12472018-04-0123411921204Cooperative Domain Formation by Homologous Motifs in HOIL-1L and SHARPIN Plays A Crucial Role in LUBAC StabilizationHiroaki Fujita0Akira Tokunaga1Satoshi Shimizu2Amanda L. Whiting3Francisco Aguilar-Alonso4Kenji Takagi5Erik Walinda6Yoshiteru Sasaki7Taketo Shimokawa8Tsunehiro Mizushima9Izuru Ohki10Mariko Ariyoshi11Hidehito Tochio12Federico Bernal13Masahiro Shirakawa14Kazuhiro Iwai15Department of Molecular and Cellular Physiology, Kyoto University School of Medicine, Kyoto 606-8501, JapanDepartment of Molecular Engineering, Kyoto University School of Engineering, Kyoto 615-8510, JapanDepartment of Anesthesia, Kyoto University Hospital, Kyoto 606-8507, JapanLaboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USALaboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USADepartment of Picobiology, University of Hyogo School of Life Science, Hyogo 678-1297, JapanDepartment of Molecular and Cellular Physiology, Kyoto University School of Medicine, Kyoto 606-8501, JapanDepartment of Molecular and Cellular Physiology, Kyoto University School of Medicine, Kyoto 606-8501, JapanDepartment of Molecular and Cellular Physiology, Kyoto University School of Medicine, Kyoto 606-8501, JapanDepartment of Picobiology, University of Hyogo School of Life Science, Hyogo 678-1297, JapanDepartment of Molecular Engineering, Kyoto University School of Engineering, Kyoto 615-8510, JapanDepartment of Molecular Engineering, Kyoto University School of Engineering, Kyoto 615-8510, JapanDepartment of Biophysics, Kyoto University School of Science, Kyoto 606-8502, JapanLaboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USADepartment of Molecular Engineering, Kyoto University School of Engineering, Kyoto 615-8510, JapanDepartment of Molecular and Cellular Physiology, Kyoto University School of Medicine, Kyoto 606-8501, Japan; Corresponding authorSummary: The linear ubiquitin chain assembly complex (LUBAC) participates in inflammatory and oncogenic signaling by conjugating linear ubiquitin chains to target proteins. LUBAC consists of the catalytic HOIP subunit and two accessory subunits, HOIL-1L and SHARPIN. Interactions between the ubiquitin-associated (UBA) domains of HOIP and the ubiquitin-like (UBL) domains of two accessory subunits are involved in LUBAC stabilization, but the precise molecular mechanisms underlying the formation of stable trimeric LUBAC remain elusive. We solved the co-crystal structure of the binding regions of the trimeric LUBAC complex and found that LUBAC-tethering motifs (LTMs) located N terminally to the UBL domains of HOIL-1L and SHARPIN heterodimerize and fold into a single globular domain. This interaction is resistant to dissociation and plays a critical role in stabilizing trimeric LUBAC. Inhibition of LTM-mediated HOIL-1L/SHARPIN dimerization profoundly attenuated the function of LUBAC, suggesting LTM as a superior target of LUBAC destabilization for anticancer therapeutics. : Fujita et al. report a crystal structure of the trimeric LUBAC core and show that motifs in HOIL-1L and SHARPIN fold into a single domain critical for LUBAC stabilization. The authors also develop an inhibitor of this interaction that destabilizes LUBAC and kills cancer cells. Keywords: linear ubiquitin chains, LUBAC, LUBAC-tethering motif, HOIP, HOIL-1L, SHARPIN, ubiquitin-like domain, ubiquitin-associated domain, cancerhttp://www.sciencedirect.com/science/article/pii/S2211124718304881 |
| spellingShingle | Hiroaki Fujita Akira Tokunaga Satoshi Shimizu Amanda L. Whiting Francisco Aguilar-Alonso Kenji Takagi Erik Walinda Yoshiteru Sasaki Taketo Shimokawa Tsunehiro Mizushima Izuru Ohki Mariko Ariyoshi Hidehito Tochio Federico Bernal Masahiro Shirakawa Kazuhiro Iwai Cooperative Domain Formation by Homologous Motifs in HOIL-1L and SHARPIN Plays A Crucial Role in LUBAC Stabilization Cell Reports |
| title | Cooperative Domain Formation by Homologous Motifs in HOIL-1L and SHARPIN Plays A Crucial Role in LUBAC Stabilization |
| title_full | Cooperative Domain Formation by Homologous Motifs in HOIL-1L and SHARPIN Plays A Crucial Role in LUBAC Stabilization |
| title_fullStr | Cooperative Domain Formation by Homologous Motifs in HOIL-1L and SHARPIN Plays A Crucial Role in LUBAC Stabilization |
| title_full_unstemmed | Cooperative Domain Formation by Homologous Motifs in HOIL-1L and SHARPIN Plays A Crucial Role in LUBAC Stabilization |
| title_short | Cooperative Domain Formation by Homologous Motifs in HOIL-1L and SHARPIN Plays A Crucial Role in LUBAC Stabilization |
| title_sort | cooperative domain formation by homologous motifs in hoil 1l and sharpin plays a crucial role in lubac stabilization |
| url | http://www.sciencedirect.com/science/article/pii/S2211124718304881 |
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