Novel Family of Insect Salivary Inhibitors Blocks Contact Pathway Activation by Binding to Polyphosphate, Heparin, and Dextran Sulfate

Novel Family of Insect Salivary Inhibitors Blocks Contact Pathway Activation by Binding to Polyphosphate, Heparin, and Dextran Sulfate

Author Alvarenga, Patricia H. Google Scholar
Xu, Xueqing Google Scholar
Oliveira, Fabiano Google Scholar
Chagas, Andrezza C. Google Scholar
Nascimento, Clarissa R. Google Scholar
Francischetti, Ivo M. B. Google Scholar
Juliano, Maria Aparecida Autor UNIFESP Google Scholar
Juliano, Luiz Autor UNIFESP Google Scholar
Scharfstein, Julio Google Scholar
Valenzuela, Jesus G. Google Scholar
Ribeiro, Jose M. C. Google Scholar
Andersen, John F. Google Scholar
Institution NIAID
Universidade Federal do Rio de Janeiro (UFRJ)
Universidade Federal de São Paulo (UNIFESP)
Abstract Objective Polyphosphate and heparin are anionic polymers released by activated mast cells and platelets that are known to stimulate the contact pathway of coagulation. These polymers promote both the autoactivation of factor XII and the assembly of complexes containing factor XI, prekallikrein, and high-molecular-weight kininogen. We are searching for salivary proteins from blood-feeding insects that counteract the effect of procoagulant and proinflammatory factors in the host, including elements of the contact pathway.Approach and Results Here, we evaluate the ability of the sand fly salivary proteins, PdSP15a and PdSP15b, to inhibit the contact pathway by disrupting binding of its components to anionic polymers. We attempt to demonstrate binding of the proteins to polyphosphate, heparin, and dextran sulfate. We also evaluate the effect of this binding on contact pathway reactions. We also set out to determine the x-ray crystal structure of PdSP15b and examine the determinants of relevant molecular interactions. Both proteins bind polyphosphate, heparin, and dextran sulfate with high affinity. Through this mechanism they inhibit the autoactivation of factor XII and factor XI, the reciprocal activation of factor XII and prekallikrein, the activation of factor XI by thrombin and factor XIIa, the cleavage of high-molecular-weight kininogen in plasma, and plasma extravasation induced by polyphosphate. the crystal structure of PdSP15b contains an amphipathic helix studded with basic side chains that forms the likely interaction surface.Conclusions the results of these studies indicate that the binding of anionic polymers by salivary proteins is used by blood feeders as an antihemostatic/anti-inflammatory mechanism.
Keywords blood coagulation factor inhibitors
bradykinin
factor XI
factor XII
inflammation
kallikreins
leishmania
Language English
Sponsor National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health
Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
US Department of Energy, Office of Science, Office of Basic Energy Sciences
Grant number US Department of Energy, Office of Science, Office of Basic Energy Sciences: W-31-109-Eng-38
Date 2013-12-01
Published in Arteriosclerosis Thrombosis and Vascular Biology. Philadelphia: Lippincott Williams & Wilkins, v. 33, n. 12, p. 2759-2770, 2013.
ISSN 1079-5642 (Sherpa/Romeo, impact factor)
Publisher Lippincott Williams & Wilkins
Extent 2759-2770
Origin http://dx.doi.org/10.1161/ATVBAHA.113.302482
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000329283900012
URI http://repositorio.unifesp.br/handle/11600/37013

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