Article (Scientific journals)
Inhibition of αIIbβ3 Ligand Binding by an αIIb Peptide that Clasps the Hybrid Domain to the βI Domain of β3
Lee, Wen Hwa; Schaffner, Elisabeth; Tsoukatos, Demokritos C et al.
2015In PLoS ONE
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journal.pone.0134952 PLOS ONE.pdf
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Abstract :
[en] Agonist-stimulated platelet activation triggers conformational changes of integrin αIIbβ3, allowing fibrinogen binding and platelet aggregation. We have previously shown that an octapeptide, p1YMESRADR8, corresponding to amino acids 313-320 of the β-ribbon extending from the β-propeller domain of αIIb, acts as a potent inhibitor of platelet aggregation. Here we have performed in silico modelling analysis of the interaction of this peptide with αIIbβ3 in its bent and closed (not swing-out) conformation and show that the peptide is able to act as a substitute for the β-ribbon by forming a clasp restraining the β3 hybrid and βI domains in a closed conformation. The involvement of species-specific residues of the β3 hybrid domain (E356 and K384) and the β1 domain (E297) as well as an intrapeptide bond (pE315-pR317) were confirmed as important for this interaction by mutagenesis studies of αIIbβ3 expressed in CHO cells and native or substituted peptide inhibitory studies on platelet functions. Furthermore, NMR data corroborate the above results. Our findings provide insight into the important functional role of the αIIb β-ribbon in preventing integrin αIIbβ3 head piece opening, and highlight a potential new therapeutic approach to prevent integrin ligand binding.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Lee, Wen Hwa
Schaffner, Elisabeth ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Tsoukatos, Demokritos C
Aylward, Kelly
Moussis, Vassilios
Tsirakis, Vassilios
Trypou, Paraskevi
Egot, Marion
Baruch, Dominique
Kieffer, Nelly
Bachelot-Loza, Christilla
External co-authors :
Language :
Title :
Inhibition of αIIbβ3 Ligand Binding by an αIIb Peptide that Clasps the Hybrid Domain to the βI Domain of β3
Publication date :
02 September 2015
Journal title :
Publisher :
Public Library of Science, San Franscisco, United States - California
Peer reviewed :
Peer Reviewed verified by ORBi
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