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J Biol Chem, Vol. 274, Issue 40, 28198-28205, October 1, 1999
From the Tat protein, a transactivating factor of the
human immunodeficiency virus type I, acts also as an extracellular
molecule. Heparin affects the bioavailability and biological activity
of extracellular Tat (Rusnati, M., Coltrini, D., Oreste, P., Zoppetti, G., Albini, A., Noonan, D., D'Adda di Fagagna, F., Giacca, M., and
Presta, M. (1997) J. Biol. Chem. 272, 11313-11320).
Here, a series of homogeneously sized, 3H-labeled heparin
fragments were evaluated for their capacity to bind to free glutathione
S-transferase (GST)-Tat protein and to immobilized GST-Tat.
Hexasaccharides represent the minimum sized heparin fragments able to
interact with GST-Tat at physiological ionic strength. Also, the
affinity of binding increases with increasing the molecular size of the
oligosaccharides, with large fragments ( The data demonstrate that the modality of heparin-Tat interaction is
strongly affected by the size of the saccharide chain. The possibility
of establishing multiple interactions increases the affinity of large
heparin fragments for Tat protein and the capacity of the
glycosaminoglycan to modulate the biological activity of extracellular Tat.
Multiple Interactions of HIV-I Tat Protein with Size-defined
Heparin Oligosaccharides
,,,
, and
Unit of General Pathology and Immunology,
Department of Biomedical Sciences and Biotechnology, School of
Medicine, University of Brescia, 25123 Brescia, Italy,
¶ Glycores 2000, 20100 Milan, Italy, the § Department
of Medical Biochemistry and Microbiology, Unit of Biochemistry, Uppsala
University, Biomedical Center, S-75123 Uppsala, Sweden, and the
International Center for Genetic Engineering and Biotechnology,
34012 Trieste, Italy
18 saccharides) approaching
the affinity of full-size heparin. 6-Mer heparin binds GST-Tat with a
dissociation constant (Kd) equal to 0.7 ± 0.4 µM and a molar oligosaccharide:GST-Tat ratio of about
1:1. Interaction of GST-Tat with 22-mer or full-size heparin is
consistent instead with two-component binding. At subsaturating concentrations, a single molecule of heparin interacts with 4-6 molecules of GST-Tat with high affinity (Kd values
in the nanomolar range of concentration); at saturating concentrations, heparin binds GST-Tat with lower affinity (Kd
values in the micromolar range of concentration) and a molar
oligosaccharide:GST-Tat ratio of about 1:1. In agreement with the
binding data, a positive correlation exists between the size of heparin
oligosaccharides and their capacity to inhibit cell internalization,
long terminal repeat-transactivating activity of extracellular Tat in
HL3T1 cells, and its mitogenic activity in murine adenocarcinoma T53 Tat-less cells.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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