The interaction of the transforming growth factor-betas with heparin/heparan sulfate is isoform-specific.
We have undertaken a comparative study of the interaction of the three mammalian transforming growth factor-betas (TGF-beta) with heparin and heparan sulfate. TGF-beta1 and -beta2, but not -beta3, bind to heparin and the highly sulfated liver heparan sulfate. These polysaccharides potentiate the biological activity of TGF-beta1 (but not the other isoforms), whereas a low sulfated mucosal heparan sulfate fails to do so. Potentiation is due to antagonism of the binding and inactivation of TGF-beta1 by alpha2-macroglobulin, rather than by modulation of growth factor-receptor interactions. TGF-beta2.alpha2-macroglobulin complexes are more refractory to heparin/heparan sulfate, and those involving TGF-beta3 cannot be affected. Comparison of the amino acid sequences of the TGF-beta isoforms strongly implicates the basic amino acid residue at position 26 of each monomer as being a vital binding determinant. A model is proposed in which polysaccharide binding occurs at two distinct sites on the TGF-beta dimer. Interaction with heparin and liver heparan sulfate may be most effective because of the ability of the dimer to co-operatively engage two specific sulfated binding sequences, separated by a distance of approximately seven disaccharides, within the same chain.
Lyon
M
M
Cancer Research Campaign/University of Manchester Department of Medical Oncology, Christie Hospital National Health Service Trust, Manchester M20 4BX, United Kingdom. monmal@picr.cr.man.ac.uk
Rushton
G
G
Gallagher
J T
JT
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002846:Chromatography, Affinity; D002851:Chromatography, High Pressure Liquid; D019281:Dimerization; D006493:Heparin / Q000737:chemistry* / Q000378:metabolism; D006497:Heparan Sulfate / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa; D008099:Liver; D008168:Lung; D008322:Mammals; D051379:Mice; D008961:Models, Structural; D011485:Protein Binding; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D016415:Sequence Alignment; D016212:Transforming Growth Factor beta / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000511:alpha-Macroglobulins / Q000737:chemistry / Q000378:metabolism
D006493:Heparin; D006497:Heparan Sulfate; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D000511:alpha-Macroglobulins