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Imaging Integrin Tension and Cellular Force at Submicron Resolution with an Integrative Tension Sensor
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Three-Dimensional Structures of Full-Length, Membrane-Embedded Human α(IIb)β(3) Integrin Complexes
Xiao-Ping Xu1, Eldar Kim1, Mark Swift1
1Bioinformatics and Structural Biology Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
Biophysical Journal
|February 25, 2016
Summary
Human integrin αIIbβ3 exists in four main conformations, shifting towards an upright state when activated by talin and ligands. This reveals new insights into integrin structure and activation mechanisms.
Area of Science:
- Structural biology
- Biochemistry
- Cell biology
Background:
- Integrins are crucial transmembrane receptors involved in hemostasis and arterial thrombosis.
- Understanding integrin conformational dynamics is key to deciphering their function in health and disease.
Purpose of the Study:
- To determine the three-dimensional structures of human integrin αIIbβ3 in near-physiological conditions.
- To investigate the conformational equilibrium of integrin αIIbβ3 in the presence of cytosolic regulators and extracellular ligands.
Main Methods:
- Cryo-electron microscopy
- Multireference single-particle reconstruction
- Computational fitting approaches
- Lipid bilayer nanodiscs
Main Results:
- Identified four main conformational states of integrin αIIbβ3, ranging from bent to fully upright.
- Demonstrated a significant shift towards the upright conformation upon binding talin and ligands.
- Revealed that ectodomain extension occurs without leg separation and the ligand-binding pocket remains accessible.
Conclusions:
- Integrin activation involves shifts in conformational equilibrium, influenced by cytosolic and extracellular factors.
- The study provides unprecedented 3D structural data of intact integrins under near-physiological conditions.
- Findings suggest integrin activation mechanisms are linked to dynamic conformational changes within the membrane bilayer.
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