Disordered Motifs and Domains in Cell Control - October 11-15, 2014

Disordered Motifs and Domains in Cell Control

Poster Session II

46-POS Board 22 Structural Interactions between Integrin αIIbβ3 and Calcium- and Integrin-binding Protein 1 Veranika Zobnina 1 , Anthony Chubb 1 , Niamh Moran 2 , Denis Shields 1 . 1 UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland, 2 Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland. Integrins are heterodimeric transmembrane receptors that coordinate cell adhesion, migration, and extracellular matrix assembly. Platelet-specific integrin αIIbβ3 plays a critical role in hemostasis and thrombosis, and regulation of its activation state represents a promising novel target for anti-platelet therapy. Two highly conserved motifs in the intracellular cytoplasmic tails of integrin αIIbβ3 (KVGFFKR in αIIb and LLITIHD in β3) maintain the receptor in a default inactive state through weak interactions. Platelet activation initiates a cascade of intracellular events that lead to spatial separation of the cytoplasmic tails and activation of integrin αIIbβ3. The KVGFFKR motif of the αIIb cytoplasmic tail is also a target for multiple intracellular proteins which regulate platelet responses. It has been suggested that CIB-1 (calcium- and integrin-binding protein 1) activates integrin αIIbβ3 and maintains the activated state of the receptor by covering the KVGFFKR motif of αIIb and preventing it's association with β3. Apo- CIB-1 is a molten globule, but upon binding of divalent ions (Ca 2+ or Mg 2+ ) it adopts stable conformation and increases it's affinity to the αIIb cytoplasmic tail. C-terminal extension of the Ca 2+ -CIB-1 structure undergoes large conformational changes upon binding to αIIb and regulates CIB-1 specificity by partially covering the binding pocket in an unbound ligand-free state. Extensive experimental studies on molecular interactions of CIB-1 with αIIb have been reported, but the structure of the CIB-1/αIIb complex remains unclear. Molecular docking, virtual screening and molecular dynamics simulations were used to elucidate and analyze the structure of CIB-1/αIIb complex and to discover molecules interacting with the binding region of CIB-1.

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