Interaction of transforming growth factor-beta 1 with alpha 2-macroglobulin. Role in transforming growth factor-beta 1 clearance.
It has been widely assumed that the interaction of transforming growth factor-beta 1 (TGF-beta 1) with its serum-binding protein, alpha 2-macroglobulin (alpha 2M), mediates the rapid clearance of TGF-beta 1 from the circulation. To test this, we have analyzed the effect of TGF-beta 1 binding on the conformational state of alpha 2M. Our results demonstrate that the binding of TGF-beta 1 to alpha 2M does not lead to the conformational change in the alpha 2M molecule that is required for the clearance of the alpha 2M.TGF-beta 1 complex via the alpha 2M receptor. Furthermore, endogenous TGF-beta 1 is associated with the conformationally unaltered slow clearance form of alpha 2M. Clearance studies in mice show that the half-life of 125I-TGF-beta 1 in the circulation (1.6 +/- 0.71 min) is not affected by blocking the alpha 2M receptor with excess conformationally altered alpha 2M. These results suggest that TGF-beta 1 is rapidly cleared from the circulation after injection by a pathway not involving alpha 2M.
Philip
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Section of Protein Engineering, National Research Council of Canada, Montreal, Quebec.
O'Connor-McCourt
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D000818:Animals; D001345:Autoradiography; D015153:Blotting, Western; D002852:Chromatography, Ion Exchange; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes; D008657:Metabolic Clearance Rate; D008744:Methylamines / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D011487:Protein Conformation; D013552:Swine; D014018:Tissue Distribution; D016212:Transforming Growth Factor beta / Q000302:isolation & purification / Q000378:metabolism* / Q000493:pharmacokinetics; D014357:Trypsin; D000511:alpha-Macroglobulins / Q000302:isolation & purification / Q000378:metabolism*
D007457:Iodine Radioisotopes; D008744:Methylamines; D016212:Transforming Growth Factor beta; D000511:alpha-Macroglobulins; C027451:methylamine; D014357:Trypsin