The Role of Arginine in Thrombin Receptor Tethered-Ligand Peptide in Intramolecular Receptor Binding and Self-Activation

Synthetic heptapeptide of the human thrombin receptor tethered-ligand peptide, H–Ser–Phe–Leu–Leu–Arg–Asn–Pro–NH2 (SFLLRNP), activates fully the thrombin receptor without thrombin. The functional role of Arg-5 was examined using a series of analogs having amino acid substitutions at position 5 in thi...

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Veröffentlicht in:Bulletin of the Chemical Society of Japan 1998-07, Vol.71 (7), p.1661-1665
Hauptverfasser: Nose, Takeru, Satoh, Yusuke, Fujita, Tsugumi, Ohno, Motonori, Nakajima, Masahide, Inoue, Yoshihisa, Ogino, Yoshio, Costa, Tommaso, Shimohigashi, Yasuyuki
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Sprache:eng
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Zusammenfassung:Synthetic heptapeptide of the human thrombin receptor tethered-ligand peptide, H–Ser–Phe–Leu–Leu–Arg–Asn–Pro–NH2 (SFLLRNP), activates fully the thrombin receptor without thrombin. The functional role of Arg-5 was examined using a series of analogs having amino acid substitutions at position 5 in this assays was to assess the abilities to hydrolyze phosphoinositide in human neuroblastoma SH-EP cells and to aggregate the human platelet. The replacement of Arg-5 by Ala reduced the activity (9% activity of the parent peptide) in the PI-turnover assay, and abolished completely the platelet aggregation activity. SFLL/Lys/NP was also active, but moderately: 36% in PI-turnover and 12% in platelet aggregation. These results indicated that the electrostatic interaction of the Arg-guanidino group is important for a peptide to interact with the receptor. When citrulline or glutamine was placed at position 5 instead of arginine, the resulting SFLL/citrulline/NP and SFLL/Gln/NP were found to be potent in both assays. Since citrulline and glutamine possess a side chain which can serve as hydrogen donor and/or acceptor, the receptor activation of these peptides appears to be due to hydrogen bonding at this position. The molecular mechanisms to explain both electrostatic and hydrogen-bonding interactions were postulated based on the structural modeling of seven-transmembrane domain thrombin receptor.
ISSN:0009-2673
1348-0634
DOI:10.1246/bcsj.71.1661