4.1 Article

Integrin αIIbβ3 Activation and Clustering in Minimal Synthetic Cells

Journal

ADVANCED NANOBIOMED RESEARCH
Volume 2, Issue 4, Pages -

Publisher

WILEY-V C H VERLAG GMBH
DOI: 10.1002/anbr.202100094

Keywords

cell adhesion; focal adhesion; integrin; integrin clustering; synthetic cell

Funding

  1. European Research Council [294852]
  2. MaxSynBio Consortium - Federal Ministry of Education and Research of Germany
  3. MaxSynBio Consortium - Max Planck Society
  4. German Science Foundation [SFB 1129]
  5. Volkswagen Stiftung
  6. Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) via the Excellence Cluster 3D Matter Made to Order at Heidelberg University [EXC-2082/1-390761711]
  7. Israel Science Foundation (ISF) [2749/17]
  8. Projekt DEAL

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This study utilizes droplet-based microfluidics to generate cell-sized giant unilamellar vesicles (GUVs) with a defined molecular composition, and quantifies the adhesion of integrin alpha(IIb)beta(3)-containing protocells in relation to the number of integrin-talin head domain (THD) complexes. The study shows that THD induces integrin clustering in protocells adhering to fibrinogen, which is an essential step in synthetic cell design. These results pave the way for further investigations of protein-protein interactions and assembly mechanisms within complex synthetic cells.
Platelet adhesion and activation are mediated by integrin alpha(IIb)beta(3) clustering, which is crucial for the hemostatic function of platelets. In an activated state, integrins provide the connection between the extracellular matrix and the actin cytoskeleton through a variety of cytoplasmic proteins, such as talin. Here, droplet-based microfluidics is applied to generate cell-sized giant unilamellar vesicles (GUVs) with a defined molecular composition to quantify the adhesion of integrin alpha(IIb)beta(3)-containing protocells in relation to the number of integrin-talin head domain (THD) complexes. Furthermore, it is shown that THD induces integrin clustering in protocells adhering to fibrinogen. The formation of this molecular link, which has, so far, only been observed in vivo, is an essential step in synthetic cell design to recapitulate integrin-mediated bidirectional signaling across the membrane. These results pave the way for further quantitative investigations of protein-protein interactions between integrins and associated proteins and their assembly within such defined, but complex, synthetic cells. An essential future step to mimic the complex interaction between cells and their environment will be to combine synthetic approaches with peptide chemistry to guide the molecular mechanisms involved in integrin binding and activation.

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