C-terminal opening mimics 'inside-out' activation of integrin alpha5beta1.
Integrins are adhesion molecules that convey signals both to and from the cytoplasm across the plasma membrane. In resting cells, integrins in a low affinity state can be activated by 'inside-out signaling', in which signals affecting integrin heterodimer cytoplasmic domains cause a conformational change in the integrin ligand-binding headpiece connected to the membrane by two long, approximately 16 nm stalks. Here we demonstrate a mechanism for conveying a conformational change over the long distance from the plasma membrane to the headpiece. We prepared soluble, alpha5beta1 integrin heterodimer extracellular fragments in which interactions between alpha- and beta-subunit cytoplasmic domains were replaced with an artificial clasp. Release of this C-terminal clasp by specific protease cleavage resulted in an approximately 14 nm separation of the stalks coupled to increased binding to fibronectin. This activation did not require any associated molecules or clustering and was observed with physiological concentrations of divalent cations. These findings suggest that the overall mechanism for integrin inside-out activation involves the spatial separation of the cytoplasmic and/or transmembrane domains.
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Related Subject Headings
- Solubility
- Signal Transduction
- Receptors, Fibronectin
- Protein Subunits
- Protein Structure, Tertiary
- Protein Engineering
- Protein Binding
- Peptide Fragments
- Molecular Sequence Data
- Models, Biological
Citation
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Solubility
- Signal Transduction
- Receptors, Fibronectin
- Protein Subunits
- Protein Structure, Tertiary
- Protein Engineering
- Protein Binding
- Peptide Fragments
- Molecular Sequence Data
- Models, Biological