Open AccessStructural basis of human full-length kindlin-3 homotrimer in an auto-inhibited state
Author(s) -
Wenting Bu,
Zarina Levitskaya,
Zhi Yang Loh,
Shengyang Jin,
Shibom Basu,
Rya Ero,
Xin-Fu Yan,
Meitian Wang,
So Fong Cam Ngan,
Siu Kwan Sze,
Suet-Mien Tan,
YongGui Gao
Publication year - 2020
Publication title -
plos biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.127
H-Index - 271
eISSN - 1545-7885
pISSN - 1544-9173
DOI - 10.1371/journal.pbio.3000755
Subject(s) - biology , pleckstrin homology domain , microbiology and biotechnology , integrin , hek 293 cells , trimer , plasma protein binding , population , integrin, beta 6 , cell adhesion , biochemistry , signal transduction , cell , chemistry , receptor , dimer , demography , organic chemistry , sociology
Kindlin-1, -2, and -3 directly bind integrin β cytoplasmic tails to regulate integrin activation and signaling. Despite their functional significance and links 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 subdomain of 1 protomer is occluded by the pleckstrin homology (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 reconstituted with the mutant kindlin-3 containing trimer-disrupting mutations exhibited an increase in integrin-mediated adhesion and spreading on fibronectin compared with those reconstituted with wild-type kindlin-3. Taken together, our findings reveal a novel mechanism of kindlin auto-inhibition that involves its homotrimer formation.