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 links to several diseases, structural information on full-length kindlin proteins remains unknown. Here, we report the crystal structure of human...

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Bibliographic Details
Published in:PLoS biology 2020-07, Vol.18 (7), p.e3000755-e3000755
Main 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
Format: Article
Language:English
Subjects:
Biology
Biology and Life Sciences
Cell adhesion & migration
Cell Movement
Crystal structure
Crystallization
Erythroleukemia
Fibronectin
Homology
Humans
Insects
Integrins - metabolism
K562 Cells
Lipids
Membrane Proteins - antagonists & inhibitors
Membrane Proteins - chemistry
Membrane Proteins - metabolism
Models, Molecular
Mutation
Neoplasm Proteins - antagonists & inhibitors
Neoplasm Proteins - chemistry
Neoplasm Proteins - metabolism
Physical Sciences
Pleckstrin
Protein Binding
Protein Domains
Protein Multimerization
Research and Analysis Methods
Structural Homology, Protein
Structure-Activity Relationship
Trimers
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Summary: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.
ISSN:1545-7885
1544-9173
1545-7885
DOI:10.1371/journal.pbio.3000755