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Intracellular Signaling Affects Focal Adhesions01:17

Intracellular Signaling Affects Focal Adhesions

Integrins act both as extracellular input receivers and as intracellular processing activators. As their name suggests, integrins are entirely integrated into the membrane structure. Their hydrophobic membrane-spanning regions interact with the phospholipid bilayer's hydrophobic region. These membrane receptors provide extracellular attachment sites for effectors like hormones and growth factors. They activate intracellular response cascades when their effectors are bound and active.
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The cadherins were one of the first cell adhesion molecules discovered; the term “cadherins”   is based on their calcium-dependent adhering properties. The first cadherins discovered on the epithelial, neuronal, and placental cells were named E-cadherin, P-cadherin, and N-cadherin, respectively. These classical cadherins share sequence and structural similarities. Other cadherins, including those involved in cell signaling, are grouped into non-classical cadherins. This diversity of cadherins...

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An Endothelial Planar Cell Model for Imaging Immunological Synapse Dynamics
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Structural framework of c-Src activation by integrin β3.

Run Xiao1, Xiao-Dong Xi, Zhu Chen

  • 1State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.

Blood
|November 22, 2012
PubMed
Summary
This summary is machine-generated.

Integrin β3 activates c-Src kinase through its SH3 domain using a novel RGT peptide interaction. This structural insight reveals a new mechanism for c-Src activation, crucial for understanding thrombosis and cancer cell migration.

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10:26

Biotinylated Cell-penetrating Peptides to Study Intracellular Protein-protein Interactions

Published on: December 20, 2017

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Biochemistry

Background:

  • Integrin β3-mediated c-Src activation is linked to diseases like thrombosis and tumor cell migration.
  • c-Src activation typically involves proline-rich sequences binding to its SH3 domain.
  • Integrin β3 utilizes a distinct RGT peptide for c-Src priming and activation, but the mechanism was unclear.

Purpose of the Study:

  • To elucidate the structural basis of integrin β3 RGT peptide binding to the c-Src SH3 domain.
  • To understand the mechanism by which the RGT peptide primes and activates c-Src.

Main Methods:

  • X-ray crystallography to determine the SH3:RGT peptide complex structure at 2.0 Å resolution.
  • Structure-based site-directed mutagenesis to validate the binding site and interaction.
  • Molecular simulations of the c-Src:β3 complex to infer activation mechanisms.

Main Results:

  • The crystal structure revealed that the RGT peptide binds to the "N"-Src loop of the SH3 domain.
  • Mutagenesis confirmed the "N"-Src loop's critical role in the SH3:RGT interaction.
  • Simulations suggest RGT binding disrupts intramolecular interactions, leading to c-Src activation.

Conclusions:

  • The RGT peptide binds to a novel site on the c-Src SH3 domain, distinct from canonical proline-rich sequences.
  • This interaction mechanism provides new insights into integrin β3-mediated c-Src activation.
  • Understanding this pathway may offer therapeutic targets for diseases involving aberrant c-Src activity.