The insect salivary protein, prolixin-S, inhibits factor IXa generation and Xase complex formation in the blood coagulation pathway.
Prolixin-S is a salivary anticoagulant of the blood-sucking insect, Rhodnius prolixus, and known as an inhibitor of the intrinsic Xase. We report here its inhibitory mechanisms with additional important anticoagulation activities. We found prolixin-S specifically bound to factor IX/IXa in the presence of Ca(2+) ions. Light scattering and surface plasmon resonance studies showed that prolixin-S interfered with factor IX/IXa binding to the phospholipid membrane, indicating that prolixin-S inhibit Xase activity of factor IXa by interference with its Xase complex formation. Furthermore, reconstitution experiments showed that prolixin-S binding to factor IX strongly inhibited factor IXa generation by factor XIa. We also found that prolixin-S inhibited factor IXa generation by factor VIIa-tissue factor complex and factor IXalpha generation by factor Xa. These results suggest that prolixin-S inhibits both intrinsic and extrinsic coagulations by sequential inhibition of all coagulation pathways in which factor IX participates. It was also suggested that prolixin-S may bind to factor IX/IXa by recognizing conformational change of the Gla domain induced by Ca(2+) binding.
Isawa
H
H
Department of Medical Zoology, School of Medicine, Mie University, 2-174 Edobashi, Tsu 514-0001, Japan.
Yuda
M
M
Yoneda
K
K
Chinzei
Y
Y
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004791:Enzyme Inhibitors; D015949:Factor IXa / Q000378:metabolism*; D015942:Factor VIIa / Q000378:metabolism; D015945:Factor XIa / Q000378:metabolism; D006420:Hemeproteins / Q000494:pharmacology*; D006801:Humans; D019476:Insect Proteins / Q000494:pharmacology; D007700:Kinetics; D009363:Neoplasm Proteins; D010743:Phospholipids / Q000378:metabolism; D011485:Protein Binding; D012239:Rhodnius / Q000378:metabolism; D012471:Salivary Proteins and Peptides / Q000494:pharmacology*; D012542:Scattering, Radiation; D020349:Surface Plasmon Resonance; D013925:Thromboplastin / Q000378:metabolism
D000925:Anticoagulants; D004791:Enzyme Inhibitors; D006420:Hemeproteins; D019476:Insect Proteins; D009363:Neoplasm Proteins; D010743:Phospholipids; D012471:Salivary Proteins and Peptides; C090560:nitrophorin; D013925:Thromboplastin; D015942:Factor VIIa; D015949:Factor IXa; D015945:Factor XIa; D003546:Cysteine Endopeptidases; C030910:cancer procoagulant; D002118:Calcium