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Volume 272, Number 17, Issue of April 25, 1997 pp. 11313-11320
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Interaction of HIV-1 Tat Protein with Heparin
ROLE OF THE BACKBONE STRUCTURE, SULFATION, AND SIZE

(Received for publication, November 14, 1996, and in revised form, January 16, 1997)

Marco Rusnati , Daniela Coltrini , Pasqua Oreste Dagger , Giorgio Zoppetti Dagger , Adriana Albini § , Douglas Noonan § , Fabrizio d'Adda di Fagagna , Mauro Giacca and Marco Presta

From the Chair of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, School of Medicine, University of Brescia, 25123 Brescia, Italy, Dagger  Glycosaminoglycan Consultants, 20100 Milan, Italy, the § Istituto Nazionale per la Ricerca sul Cancro, 16132 Genova, Italy, and the  International Centre for Genetic Engineering and Biotechnology, 34012 Trieste, Italy

Human immunodeficiency virus type 1 (HIV-1) Tat protein is released from infected cells. Extracellular Tat enters the cell where it stimulates the transcriptional activity of HIV-long terminal repeat (LTR) and of endogenous genes. Heparin modulates the angiogenic (Albini, A., Benelli, R., Presta, M., Rusnati, M., Ziche, M., Rubartelli, A., Paglialunga, G., Bussolino, F., and Noonan, D. (1996) Oncogene 12, 289-297) and transcriptional (Mann, D. A., and Frankel, A. D. (1991) EMBO J. 10, 1733-1739) activity of extracellular Tat. Here we demonstrate that heparin binds specifically to recombinant HIV-1 Tat produced as glutathione S-transferase (GST) fusion protein and immobilized on glutathione-agarose beads. Heparin and heparan sulfate (HS), but not dermatan sulfate, chondroitin sulfates A and C, hyaluronic acid, and K5 polysaccharide, competed with 3H-labeled heparin for binding to immobilized GST-Tat and inhibited HIV-LTR transactivation induced by extracellular GST-Tat.

Selective 2-O-, 6-O-, total-O-desulfation, or N-desulfation/N-acetylation dramatically reduced the capacity of heparin to bind GST-Tat. Totally-O-desulfated and 2-O-desulfated heparins also showed a reduced capacity to inhibit the transactivating activity of GST-Tat. Very low molecular weight heparins showed a significant decrease in their capacity to bind GST-Tat and to inhibit its LTR transactivating activity when compared with conventional 13.6-kDa heparin. However, when 3.0-kDa heparin was affinity chromatographed on immobilized GST-Tat to isolate binding and non-binding subfractions, the Tat-bound fraction was >= 1,000 times more potent than the unbound fraction in inhibiting the transactivating activity of GST-Tat.

The results demonstrate that Tat interacts in a size-dependent manner with heparin/HS and that high affinity Tat-heparin interaction requires at least some 2-O-, 6-O-, and N-positions to be sulfated. The Tat binding activity of the glycosaminoglycans tested correlates with their capacity to affect the transactivating activity of extracellular Tat, indicating the possibility to design specific heparin/HS-like structures with Tat-antagonist activity.


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