Chemical modification of α2‐macroglobulin to generate derivatives that bind transforming growth factor‐β with increased affinity

FEBS Letters

Gonias, Steven L.¹  Webb, Donna J.¹ 

[1]Departments of Pathology and Biochemistry, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA

关键词: α2-macroglobulin;    Transforming growth factor-β;    Cytokine;    Endothelium;   

DOI  :  10.1016/S0014-5793(97)00598-X

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

α₂-Macroglobulin (α₂M) binds a number of cytokines, including transforming growth factor-β1 (TGF-β1) and TGF-β2. The affinity of these interactions depends on the α₂M conformation. In this investigation, we treated human α₂M with cis-dichlorodiammineplatinum (II) (cis-Pt), a crosslinking reagent that partially ‘locks’ the α₂M conformation, and then with methylamine to generate a preparation (α₂M-P/M) consisting of stable α₂M conformational intermediates. α₂M-P/M bound TGF-β1 and TGF-β2 with higher affinity than any other form of α₂M studied to date. The equilibrium dissociation constants were 14 and 2 nM for TGF-β1 and TGF-β2, respectively. α₂M-P/M, at 100 nM, neutralized the activity of TGF-β1 by about 75% in an endothelial cell proliferation assay. The equivalent concentration of native α₂M or methylamine-modified α₂M had no effect. These studies demonstrate that the potential of α₂M as a cytokine carrier and neutralizer may not be fully realized in either the native or completely activated conformations.

【 授权许可】

Unknown