Structural highlights
Function
[PLF4_HUMAN] Released during platelet aggregation. Neutralizes the anticoagulant effect of heparin because it binds more strongly to heparin than to the chondroitin-4-sulfate chains of the carrier molecule. Chemotactic for neutrophils and monocytes. Inhibits endothelial cell proliferation, the short form is a more potent inhibitor than the longer form.[1]
Publication Abstract from PubMed
Heparin-induced thrombocytopenia (HIT) is an autoimmune thrombotic disorder caused by immune complexes containing platelet factor 4 (PF4), antibodies to PF4 and heparin or cellular glycosaminoglycans (GAGs). Here we solve the crystal structures of the: (1) PF4 tetramer/fondaparinux complex, (2) PF4 tetramer/KKO-Fab complex (a murine monoclonal HIT-like antibody) and (3) PF4 monomer/RTO-Fab complex (a non-HIT anti-PF4 monoclonal antibody). Fondaparinux binds to the 'closed' end of the PF4 tetramer and stabilizes its conformation. This interaction in turn stabilizes the epitope for KKO on the 'open' end of the tetramer. Fondaparinux and KKO thereby collaborate to 'stabilize' the ternary pathogenic immune complex. Binding of RTO to PF4 monomers prevents PF4 tetramerization and inhibits KKO and human HIT IgG-induced platelet activation and platelet aggregation in vitro, and thrombus progression in vivo. The atomic structures provide a basis to develop new diagnostics and non-anticoagulant therapeutics for HIT.
Atomic description of the immune complex involved in heparin-induced thrombocytopenia.,Cai Z, Yarovoi SV, Zhu Z, Rauova L, Hayes V, Lebedeva T, Liu Q, Poncz M, Arepally G, Cines DB, Greene MI Nat Commun. 2015 Sep 22;6:8277. doi: 10.1038/ncomms9277. PMID:26391892[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Gupta SK, Hassel T, Singh JP. A potent inhibitor of endothelial cell proliferation is generated by proteolytic cleavage of the chemokine platelet factor 4. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7799-803. PMID:7644496
- ↑ Cai Z, Yarovoi SV, Zhu Z, Rauova L, Hayes V, Lebedeva T, Liu Q, Poncz M, Arepally G, Cines DB, Greene MI. Atomic description of the immune complex involved in heparin-induced thrombocytopenia. Nat Commun. 2015 Sep 22;6:8277. doi: 10.1038/ncomms9277. PMID:26391892 doi:http://dx.doi.org/10.1038/ncomms9277
