The Diversity and Similarity of Transmembrane Trimerization of TNF Receptors
Receptors in the tumor necrosis factor receptor superfamily (TNFRSF) regulate proliferation of immune cells or induce programmed cell death, and many of them are candidates for antibody-based immunotherapy. Previous studies on several death receptors in the TNFRSF including Fas, p75NTR, and DR5 show...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-10-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fcell.2020.569684/full |
| _version_ | 1819010882686943232 |
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| author | Linlin Zhao Qingshan Fu Liqiang Pan Alessandro Piai James J. Chou |
| author_facet | Linlin Zhao Qingshan Fu Liqiang Pan Alessandro Piai James J. Chou |
| author_sort | Linlin Zhao |
| collection | DOAJ |
| description | Receptors in the tumor necrosis factor receptor superfamily (TNFRSF) regulate proliferation of immune cells or induce programmed cell death, and many of them are candidates for antibody-based immunotherapy. Previous studies on several death receptors in the TNFRSF including Fas, p75NTR, and DR5 showed that the transmembrane helix (TMH) of these receptors can specifically oligomerize and their oligomeric states have direct consequences on receptor activation, suggesting a much more active role of TMH in receptor signaling than previously appreciated. Here, we report the structure of the TMH of TNFR1, another well studied member of the TNFRSF, in neutral bicelles that mimic a lipid bilayer. We find that TNFR1 TMH forms a defined trimeric complex in bicelles, and no evidences of higher-order clustering of trimers have been detected. Unexpectedly, a conserved proline, which is critical for Fas TMH trimerization, does not appear to play an important role in TNFR1 TMH trimerization, which is instead mediated by a glycine near the middle of the TMH. Further, TNFR1 TMH trimer shows a larger hydrophobic core than that of Fas or DR5, with four layers of hydrophobic interaction along the threefold axis. Comparison of the TNFR1 TMH structure with that of Fas and DR5 reveals reassuring similarities that have functional implications but also significant structural diversity that warrants systematic investigation of TMH oligomerization property for other members of the TNFRSF. |
| first_indexed | 2024-12-21T01:19:20Z |
| format | Article |
| id | doaj.art-1453adb81a6e4a4684271173973ded4c |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-21T01:19:20Z |
| publishDate | 2020-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-1453adb81a6e4a4684271173973ded4c2022-12-21T19:20:41ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2020-10-01810.3389/fcell.2020.569684569684The Diversity and Similarity of Transmembrane Trimerization of TNF ReceptorsLinlin ZhaoQingshan FuLiqiang PanAlessandro PiaiJames J. ChouReceptors in the tumor necrosis factor receptor superfamily (TNFRSF) regulate proliferation of immune cells or induce programmed cell death, and many of them are candidates for antibody-based immunotherapy. Previous studies on several death receptors in the TNFRSF including Fas, p75NTR, and DR5 showed that the transmembrane helix (TMH) of these receptors can specifically oligomerize and their oligomeric states have direct consequences on receptor activation, suggesting a much more active role of TMH in receptor signaling than previously appreciated. Here, we report the structure of the TMH of TNFR1, another well studied member of the TNFRSF, in neutral bicelles that mimic a lipid bilayer. We find that TNFR1 TMH forms a defined trimeric complex in bicelles, and no evidences of higher-order clustering of trimers have been detected. Unexpectedly, a conserved proline, which is critical for Fas TMH trimerization, does not appear to play an important role in TNFR1 TMH trimerization, which is instead mediated by a glycine near the middle of the TMH. Further, TNFR1 TMH trimer shows a larger hydrophobic core than that of Fas or DR5, with four layers of hydrophobic interaction along the threefold axis. Comparison of the TNFR1 TMH structure with that of Fas and DR5 reveals reassuring similarities that have functional implications but also significant structural diversity that warrants systematic investigation of TMH oligomerization property for other members of the TNFRSF.https://www.frontiersin.org/article/10.3389/fcell.2020.569684/fullTNFR1transmembrane domainoligomerizationreceptor activationNMR |
| spellingShingle | Linlin Zhao Qingshan Fu Liqiang Pan Alessandro Piai James J. Chou The Diversity and Similarity of Transmembrane Trimerization of TNF Receptors Frontiers in Cell and Developmental Biology TNFR1 transmembrane domain oligomerization receptor activation NMR |
| title | The Diversity and Similarity of Transmembrane Trimerization of TNF Receptors |
| title_full | The Diversity and Similarity of Transmembrane Trimerization of TNF Receptors |
| title_fullStr | The Diversity and Similarity of Transmembrane Trimerization of TNF Receptors |
| title_full_unstemmed | The Diversity and Similarity of Transmembrane Trimerization of TNF Receptors |
| title_short | The Diversity and Similarity of Transmembrane Trimerization of TNF Receptors |
| title_sort | diversity and similarity of transmembrane trimerization of tnf receptors |
| topic | TNFR1 transmembrane domain oligomerization receptor activation NMR |
| url | https://www.frontiersin.org/article/10.3389/fcell.2020.569684/full |
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