Structural basis of human full-length kindlin-3 homotrimer in an auto-inhibited state.
- Bu W School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
- Levitskaya Z School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
- Loh ZY School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
- Jin S School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
- Basu S Swiss Light Source, Paul Scherrer Institute, Villigen, Switzerland.
- Ero R School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
- Yan X School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
- Wang M Swiss Light Source, Paul Scherrer Institute, Villigen, Switzerland.
- Ngan SFC School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
- Sze SK School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
- Tan SM School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
- Gao YG School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
- 2020-07-10
Published in:
- PLoS biology. - 2020
Cell Movement
Humans
Integrins
K562 Cells
Membrane Proteins
Models, Molecular
Neoplasm Proteins
Protein Binding
Protein Domains
Protein Multimerization
Structural Homology, Protein
Structure-Activity Relationship
English
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.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1371/journal.pbio.3000755
- PMID 32644996
- Persistent URL
- https://sonar.ch/global/documents/1065
Statistics
Document views: 26
File downloads:
- Full-text: 0