Structural basis of human full-length kindlin-3 homotrimer in an auto-inhibited state.
Journal
PLoS biology
ISSN: 1545-7885
Titre abrégé: PLoS Biol
Pays: United States
ID NLM: 101183755
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
07
08
2019
accepted:
22
06
2020
revised:
21
07
2020
pubmed:
10
7
2020
medline:
25
8
2020
entrez:
10
7
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32644996
doi: 10.1371/journal.pbio.3000755
pii: PBIOLOGY-D-19-02291
pmc: PMC7373317
doi:
Substances chimiques
FERMT3 protein, human
0
Integrins
0
Membrane Proteins
0
Neoplasm Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e3000755Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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