The C-terminal fragment of axon guidance molecule Slit3 binds heparin and neutralizes heparin's anticoagulant activity.
Slit3 is a large molecule with multiple domains and belongs to axon guidance families. To date, the biological functions of Slit3 are still largely unknown. Our recent study demonstrated that the N-terminal fragment of Slit3 is a novel angiogenic factor. In this study, we examined the biological function of the C-terminal fragment of human Slit3 (HSCF). The HSCF showed a high-affinity binding to heparin. The binding appeared to be heparin/heparan sulfate-specific and depends on the size, the degree of sulfation, the presence of N- and 6-O-sulfates and carboxyl moiety of the polysaccharide. Functional studies observed that HSCF inhibited antithrombin binding to heparin and neutralized the antifactor IIa and Xa activities of heparin and the antifactor IIa activity of low-molecular-weight heparin (LMWH). Thromboelastography analysis observed that HSCF reversed heparin's anticoagulation in global plasma coagulation. Taken together, these observations demonstrate that HSCF is a novel heparin-binding protein that potently neutralizes heparin's anticoagulation activity. This study reveals a potential for HSCF to be developed as a new antidote to treat overdosing of both heparin and LMWH in clinical applications.
Department of Biochemistry and Molecular Biology, Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602-4712, USA.
Eduard
E
Condac
Heather
H
Strachan
Gerardo
G
Gutierrez-Sanchez
Benjamin
B
Brainard
Christina
C
Giese
Christian
C
Heiss
Darryl
D
Johnson
Parastoo
P
Azadi
Carl
C
Bergmann
Ron
R
Orlando
Charles T
CT
Esmon
Job
J
Harenberg
Kelley
K
Moremen
Lianchun
L
Wang
D000595:Amino Acid Sequence; D000925:Anticoagulants / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000990:Antithrombin III / Q000037:antagonists & inhibitors / Q000737:chemistry; D001665:Binding Sites; D001777:Blood Coagulation; D015951:Factor Xa / Q000737:chemistry; D065427:Factor Xa Inhibitors; D006493:Heparin / Q000737:chemistry*; D006494:Heparin Antagonists / Q000737:chemistry / Q000494:pharmacology*; D006495:Heparin, Low-Molecular-Weight / Q000037:antagonists & inhibitors / Q000737:chemistry; D006497:Heparan Sulfate / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011516:Prothrombin / Q000037:antagonists & inhibitors / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D012996:Solutions; D013916:Thrombelastography
D000925:Anticoagulants; D000990:Antithrombin III; D015951:Factor Xa; D065427:Factor Xa Inhibitors; D006493:Heparin; D006494:Heparin Antagonists; D006495:Heparin, Low-Molecular-Weight; D006497:Heparan Sulfate; D008565:Membrane Proteins; D010446:Peptide Fragments; D011516:Prothrombin; D011994:Recombinant Proteins; D012996:Solutions; C498990:SLIT3 protein, human; C025337:Factor IIa