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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