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The importance of N-glycosylation on β 3 integrin ligand binding and conformational regulation.
- Source :
-
Scientific reports [Sci Rep] 2017 Jul 05; Vol. 7 (1), pp. 4656. Date of Electronic Publication: 2017 Jul 05. - Publication Year :
- 2017
-
Abstract
- N-glycosylations can regulate the adhesive function of integrins. Great variations in both the number and distribution of N-glycosylation sites are found in the 18 α and 8 β integrin subunits. Crystal structures of α <subscript>IIb</subscript> β <subscript>3</subscript> and α <subscript>V</subscript> β <subscript>3</subscript> have resolved the precise structural location of each N-glycan site, but the structural consequences of individual N-glycan site on integrin activation remain unclear. By site-directed mutagenesis and structure-guided analyses, we dissected the function of individual N-glycan sites in β <subscript>3</subscript> integrin activation. We found that the N-glycan site, β <subscript>3</subscript> -N320 at the headpiece and leg domain interface positively regulates α <subscript>IIb</subscript> β <subscript>3</subscript> but not α <subscript>V</subscript> β <subscript>3</subscript> activation. The β <subscript>3</subscript> -N559 N-glycan at the β <subscript>3</subscript> -I-EGF3 and α <subscript>IIb</subscript> -calf-1 domain interface, and the β <subscript>3</subscript> -N654 N-glycan at the β <subscript>3</subscript> -β-tail and α <subscript>IIb</subscript> -calf-2 domain interface positively regulate the activation of both α <subscript>IIb</subscript> β <subscript>3</subscript> and α <subscript>V</subscript> β <subscript>3</subscript> integrins. In contrast, removal of the β <subscript>3</subscript> -N371 N-glycan near the β <subscript>3</subscript> hybrid and I-EGF3 interface, or the β <subscript>3</subscript> -N452 N-glycan at the I-EGF1 domain rendered β <subscript>3</subscript> integrin more active than the wild type. We identified one unique N-glycan at the βI domain of β <subscript>1</subscript> subunit that negatively regulates α <subscript>5</subscript> β <subscript>1</subscript> activation. Our study suggests that the bulky N-glycans influence the large-scale conformational rearrangement by potentially stabilizing or destabilizing the domain interfaces of integrin.
- Subjects :
- Binding Sites
Glycosylation
HEK293 Cells
Humans
Integrin alphaVbeta3 chemistry
Integrin alphaVbeta3 metabolism
Integrin beta3 genetics
Ligands
Mitochondrial Proteins chemistry
Mitochondrial Proteins metabolism
Models, Molecular
Peptide Elongation Factor G chemistry
Peptide Elongation Factor G metabolism
Platelet Glycoprotein GPIIb-IIIa Complex chemistry
Platelet Glycoprotein GPIIb-IIIa Complex metabolism
Protein Binding
Protein Conformation
Integrin beta3 chemistry
Integrin beta3 metabolism
Mutagenesis, Site-Directed
Polysaccharides metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 7
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 28680094
- Full Text :
- https://doi.org/10.1038/s41598-017-04844-w