Cryo-EM structures of pannexin 1 and 3 reveal differences among pannexin isoforms
Abstract Pannexins are single-membrane large-pore channels that release ions and ATP upon activation. Three isoforms of pannexins 1, 2, and 3, perform diverse cellular roles and differ in their pore lining residues. In this study, we report the cryo-EM structure of pannexin 3 at 3.9 Å and analyze it...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-04-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-47142-6 |
| _version_ | 1797219708009709568 |
|---|---|
| author | Nazia Hussain Ashish Apotikar Shabareesh Pidathala Sourajit Mukherjee Ananth Prasad Burada Sujit Kumar Sikdar Kutti R. Vinothkumar Aravind Penmatsa |
| author_facet | Nazia Hussain Ashish Apotikar Shabareesh Pidathala Sourajit Mukherjee Ananth Prasad Burada Sujit Kumar Sikdar Kutti R. Vinothkumar Aravind Penmatsa |
| author_sort | Nazia Hussain |
| collection | DOAJ |
| description | Abstract Pannexins are single-membrane large-pore channels that release ions and ATP upon activation. Three isoforms of pannexins 1, 2, and 3, perform diverse cellular roles and differ in their pore lining residues. In this study, we report the cryo-EM structure of pannexin 3 at 3.9 Å and analyze its structural differences with pannexin isoforms 1 and 2. The pannexin 3 vestibule has two distinct chambers and a wider pore radius in comparison to pannexins 1 and 2. We further report two cryo-EM structures of pannexin 1, with pore substitutions W74R/R75D that mimic the pore lining residues of pannexin 2 and a germline mutant of pannexin 1, R217H at resolutions of 3.2 Å and 3.9 Å, respectively. Substitution of cationic residues in the vestibule of pannexin 1 results in reduced ATP interaction propensities to the channel. The germline mutant R217H in transmembrane helix 3 (TM3), leads to a partially constricted pore, reduced ATP interaction and weakened voltage sensitivity. The study compares the three pannexin isoform structures, the effects of substitutions of pore and vestibule-lining residues and allosteric effects of a pathological substitution on channel structure and function thereby enhancing our understanding of this vital group of ATP-release channels. |
| first_indexed | 2024-04-24T12:37:56Z |
| format | Article |
| id | doaj.art-03f0c6d8635c440587287f9c5ea0736a |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-24T12:37:56Z |
| publishDate | 2024-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-03f0c6d8635c440587287f9c5ea0736a2024-04-07T11:22:55ZengNature PortfolioNature Communications2041-17232024-04-0115111410.1038/s41467-024-47142-6Cryo-EM structures of pannexin 1 and 3 reveal differences among pannexin isoformsNazia Hussain0Ashish Apotikar1Shabareesh Pidathala2Sourajit Mukherjee3Ananth Prasad Burada4Sujit Kumar Sikdar5Kutti R. Vinothkumar6Aravind Penmatsa7Molecular Biophysics Unit, Indian Institute of ScienceMolecular Biophysics Unit, Indian Institute of ScienceMolecular Biophysics Unit, Indian Institute of ScienceMolecular Biophysics Unit, Indian Institute of ScienceMolecular Biophysics Unit, Indian Institute of ScienceMolecular Biophysics Unit, Indian Institute of ScienceNational Centre for Biological Sciences, Tata Institute of Fundamental ResearchMolecular Biophysics Unit, Indian Institute of ScienceAbstract Pannexins are single-membrane large-pore channels that release ions and ATP upon activation. Three isoforms of pannexins 1, 2, and 3, perform diverse cellular roles and differ in their pore lining residues. In this study, we report the cryo-EM structure of pannexin 3 at 3.9 Å and analyze its structural differences with pannexin isoforms 1 and 2. The pannexin 3 vestibule has two distinct chambers and a wider pore radius in comparison to pannexins 1 and 2. We further report two cryo-EM structures of pannexin 1, with pore substitutions W74R/R75D that mimic the pore lining residues of pannexin 2 and a germline mutant of pannexin 1, R217H at resolutions of 3.2 Å and 3.9 Å, respectively. Substitution of cationic residues in the vestibule of pannexin 1 results in reduced ATP interaction propensities to the channel. The germline mutant R217H in transmembrane helix 3 (TM3), leads to a partially constricted pore, reduced ATP interaction and weakened voltage sensitivity. The study compares the three pannexin isoform structures, the effects of substitutions of pore and vestibule-lining residues and allosteric effects of a pathological substitution on channel structure and function thereby enhancing our understanding of this vital group of ATP-release channels.https://doi.org/10.1038/s41467-024-47142-6 |
| spellingShingle | Nazia Hussain Ashish Apotikar Shabareesh Pidathala Sourajit Mukherjee Ananth Prasad Burada Sujit Kumar Sikdar Kutti R. Vinothkumar Aravind Penmatsa Cryo-EM structures of pannexin 1 and 3 reveal differences among pannexin isoforms Nature Communications |
| title | Cryo-EM structures of pannexin 1 and 3 reveal differences among pannexin isoforms |
| title_full | Cryo-EM structures of pannexin 1 and 3 reveal differences among pannexin isoforms |
| title_fullStr | Cryo-EM structures of pannexin 1 and 3 reveal differences among pannexin isoforms |
| title_full_unstemmed | Cryo-EM structures of pannexin 1 and 3 reveal differences among pannexin isoforms |
| title_short | Cryo-EM structures of pannexin 1 and 3 reveal differences among pannexin isoforms |
| title_sort | cryo em structures of pannexin 1 and 3 reveal differences among pannexin isoforms |
| url | https://doi.org/10.1038/s41467-024-47142-6 |
| work_keys_str_mv | AT naziahussain cryoemstructuresofpannexin1and3revealdifferencesamongpannexinisoforms AT ashishapotikar cryoemstructuresofpannexin1and3revealdifferencesamongpannexinisoforms AT shabareeshpidathala cryoemstructuresofpannexin1and3revealdifferencesamongpannexinisoforms AT sourajitmukherjee cryoemstructuresofpannexin1and3revealdifferencesamongpannexinisoforms AT ananthprasadburada cryoemstructuresofpannexin1and3revealdifferencesamongpannexinisoforms AT sujitkumarsikdar cryoemstructuresofpannexin1and3revealdifferencesamongpannexinisoforms AT kuttirvinothkumar cryoemstructuresofpannexin1and3revealdifferencesamongpannexinisoforms AT aravindpenmatsa cryoemstructuresofpannexin1and3revealdifferencesamongpannexinisoforms |