Recent Advances in the Structural Biology of the Volume-Regulated Anion Channel LRRC8
Members of the leucine-rich repeat-containing 8 (LRRC8) protein family, composed of five LRRC8A-E isoforms, are pore-forming components of the volume-regulated anion channel (VRAC), which is activated by cell swelling and releases chloride ions (Cl−) or other osmolytes to counteract cell swelling. A...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.896532/full |
| _version_ | 1828285244112896000 |
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| author | Go Kasuya Osamu Nureki |
| author_facet | Go Kasuya Osamu Nureki |
| author_sort | Go Kasuya |
| collection | DOAJ |
| description | Members of the leucine-rich repeat-containing 8 (LRRC8) protein family, composed of five LRRC8A-E isoforms, are pore-forming components of the volume-regulated anion channel (VRAC), which is activated by cell swelling and releases chloride ions (Cl−) or other osmolytes to counteract cell swelling. Although the LRRC8 protein family was identified as the molecular entity of VRAC only in 2014, due to recent advances in cryo-electron microscopy (cryo-EM), various LRRC8 structures, including homo-hexameric LRRC8A and LRRC8D structures, as well as inhibitor-bound and synthetic single-domain antibody-bound homo-hexameric LRRC8A structures, have been reported, thus extending our understanding of the molecular mechanisms of this protein family. In this review, we describe the important features of LRRC8 provided by these structures, particularly the overall architectures, and the suggested mechanisms underlying pore inhibition and allosteric modulation by targeting the intracellular leucine-rich repeat (LRR) domain. |
| first_indexed | 2024-04-13T09:12:19Z |
| format | Article |
| id | doaj.art-94ae82521d374c6682ec5947dfa85190 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-13T09:12:19Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-94ae82521d374c6682ec5947dfa851902022-12-22T02:52:51ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-05-011310.3389/fphar.2022.896532896532Recent Advances in the Structural Biology of the Volume-Regulated Anion Channel LRRC8Go Kasuya0Osamu Nureki1Division of Integrative Physiology, Department of Physiology, Jichi Medical University, Shimotsuke, JapanDepartment of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, JapanMembers of the leucine-rich repeat-containing 8 (LRRC8) protein family, composed of five LRRC8A-E isoforms, are pore-forming components of the volume-regulated anion channel (VRAC), which is activated by cell swelling and releases chloride ions (Cl−) or other osmolytes to counteract cell swelling. Although the LRRC8 protein family was identified as the molecular entity of VRAC only in 2014, due to recent advances in cryo-electron microscopy (cryo-EM), various LRRC8 structures, including homo-hexameric LRRC8A and LRRC8D structures, as well as inhibitor-bound and synthetic single-domain antibody-bound homo-hexameric LRRC8A structures, have been reported, thus extending our understanding of the molecular mechanisms of this protein family. In this review, we describe the important features of LRRC8 provided by these structures, particularly the overall architectures, and the suggested mechanisms underlying pore inhibition and allosteric modulation by targeting the intracellular leucine-rich repeat (LRR) domain.https://www.frontiersin.org/articles/10.3389/fphar.2022.896532/fullstructural biologycryo-EMcell volume homeostasisVRACLRRC8 |
| spellingShingle | Go Kasuya Osamu Nureki Recent Advances in the Structural Biology of the Volume-Regulated Anion Channel LRRC8 Frontiers in Pharmacology structural biology cryo-EM cell volume homeostasis VRAC LRRC8 |
| title | Recent Advances in the Structural Biology of the Volume-Regulated Anion Channel LRRC8 |
| title_full | Recent Advances in the Structural Biology of the Volume-Regulated Anion Channel LRRC8 |
| title_fullStr | Recent Advances in the Structural Biology of the Volume-Regulated Anion Channel LRRC8 |
| title_full_unstemmed | Recent Advances in the Structural Biology of the Volume-Regulated Anion Channel LRRC8 |
| title_short | Recent Advances in the Structural Biology of the Volume-Regulated Anion Channel LRRC8 |
| title_sort | recent advances in the structural biology of the volume regulated anion channel lrrc8 |
| topic | structural biology cryo-EM cell volume homeostasis VRAC LRRC8 |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.896532/full |
| work_keys_str_mv | AT gokasuya recentadvancesinthestructuralbiologyofthevolumeregulatedanionchannellrrc8 AT osamunureki recentadvancesinthestructuralbiologyofthevolumeregulatedanionchannellrrc8 |