Structural basis of human full-length kindlin-3 homotrimer in an auto-inhibited state
Kindlin-1, -2, and -3, directly bind integrin β cytoplasmic tails to regulate integrin activation and signaling. Despite their functional significance and link to several diseases, structural information on full-length kindlin proteins remains unknown. Here, we report the crystal structure of human...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2021
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| Online Access: | https://hdl.handle.net/10356/146721 |
| _version_ | 1826114226030116864 |
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| author | Bu, Wenting Levitskaya, Zarina Loh, Zhi Yang Jin, Shengyang Basu, Shibom Ero, Rya Yan, Xinfu Wang, Meitian Ngan, So Fong Cam Sze, Siu Kwan Tan, Suet-Mien Gao, Yong-Gui |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Bu, Wenting Levitskaya, Zarina Loh, Zhi Yang Jin, Shengyang Basu, Shibom Ero, Rya Yan, Xinfu Wang, Meitian Ngan, So Fong Cam Sze, Siu Kwan Tan, Suet-Mien Gao, Yong-Gui |
| author_sort | Bu, Wenting |
| collection | NTU |
| description | Kindlin-1, -2, and -3, directly bind integrin β cytoplasmic tails to regulate integrin activation and signaling. Despite their functional significance and link to several diseases, structural information on full-length kindlin proteins remains unknown. Here, we report the crystal structure of human full-length kindlin-3, which reveals a novel homotrimer state. Unlike kindlin-3 monomer, which is the major population in insect and mammalian cell expression systems, kindlin-3 trimer does not bind integrin β cytoplasmic tail as the integrin-binding pocket in the F3 sub-domain of one protomer is occluded by the PH domain of another protomer, suggesting that kindlin-3 is auto-inhibited upon trimer formation. This is also supported by functional assays in which kindlin-3 knockout K562 erythroleukemia cells re-constituted with the mutant kindlin-3 containing trimer-disrupting mutations exhibited an increase in integrin-mediated adhesion and spreading on fibronectin compared to those re-constituted with wild type kindlin-3. Taken together, our findings reveal a novel mechanism of kindlin auto-inhibition that involves its homotrimer formation. |
| first_indexed | 2024-10-01T03:36:01Z |
| format | Journal Article |
| id | ntu-10356/146721 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T03:36:01Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | ntu-10356/1467212023-02-28T17:09:58Z Structural basis of human full-length kindlin-3 homotrimer in an auto-inhibited state Bu, Wenting Levitskaya, Zarina Loh, Zhi Yang Jin, Shengyang Basu, Shibom Ero, Rya Yan, Xinfu Wang, Meitian Ngan, So Fong Cam Sze, Siu Kwan Tan, Suet-Mien Gao, Yong-Gui School of Biological Sciences NTU Institute of Structural Biology Science::Biological sciences Kindlin FERM Kindlin-1, -2, and -3, directly bind integrin β cytoplasmic tails to regulate integrin activation and signaling. Despite their functional significance and link to several diseases, structural information on full-length kindlin proteins remains unknown. Here, we report the crystal structure of human full-length kindlin-3, which reveals a novel homotrimer state. Unlike kindlin-3 monomer, which is the major population in insect and mammalian cell expression systems, kindlin-3 trimer does not bind integrin β cytoplasmic tail as the integrin-binding pocket in the F3 sub-domain of one protomer is occluded by the PH domain of another protomer, suggesting that kindlin-3 is auto-inhibited upon trimer formation. This is also supported by functional assays in which kindlin-3 knockout K562 erythroleukemia cells re-constituted with the mutant kindlin-3 containing trimer-disrupting mutations exhibited an increase in integrin-mediated adhesion and spreading on fibronectin compared to those re-constituted with wild type kindlin-3. Taken together, our findings reveal a novel mechanism of kindlin auto-inhibition that involves its homotrimer formation. Published version 2021-03-08T08:29:11Z 2021-03-08T08:29:11Z 2020 Journal Article Bu, W., Levitskaya, Z., Loh, Z. Y., Jin, S., Basu, S., Ero, R., ... Gao, Y.-G. (2020). Structural basis of human full-length kindlin-3 homotrimer in an auto-inhibited state. PLOS Biology, 18(7): e3000755-. doi:10.1371/journal.pbio.3000755 1545-7885 https://hdl.handle.net/10356/146721 10.1371/journal.pbio.3000755 7 18 e3000755 en PLOS Biology © 2020 Bu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. application/pdf |
| spellingShingle | Science::Biological sciences Kindlin FERM Bu, Wenting Levitskaya, Zarina Loh, Zhi Yang Jin, Shengyang Basu, Shibom Ero, Rya Yan, Xinfu Wang, Meitian Ngan, So Fong Cam Sze, Siu Kwan Tan, Suet-Mien Gao, Yong-Gui Structural basis of human full-length kindlin-3 homotrimer in an auto-inhibited state |
| title | Structural basis of human full-length kindlin-3 homotrimer in an auto-inhibited state |
| title_full | Structural basis of human full-length kindlin-3 homotrimer in an auto-inhibited state |
| title_fullStr | Structural basis of human full-length kindlin-3 homotrimer in an auto-inhibited state |
| title_full_unstemmed | Structural basis of human full-length kindlin-3 homotrimer in an auto-inhibited state |
| title_short | Structural basis of human full-length kindlin-3 homotrimer in an auto-inhibited state |
| title_sort | structural basis of human full length kindlin 3 homotrimer in an auto inhibited state |
| topic | Science::Biological sciences Kindlin FERM |
| url | https://hdl.handle.net/10356/146721 |
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