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Title: Structural basis of human full-length kindlin-3 homotrimer in an auto-inhibited state
Authors: 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
Keywords: Science::Biological sciences
Issue Date: 2020
Source: 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
Journal: PLOS Biology
Abstract: 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.
ISSN: 1545-7885
DOI: 10.1371/journal.pbio.3000755
Rights: © 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.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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