Insulin-like growth factors I and II are unable to form and maintain theirnative disulfides under in vivo redox conditions

Insulin-like growth factor (IGF) I does not quantitatively form its three n ative disulfide bonds in the presence of 10 mM reduced and 1 mM oxidized gl utathione in vitro [Hober, S. et al. (1992) Biochemistry 31, 1749-1756]. In this paper, we show (i) that both IGF-I and IGF-II are unable to form and maintain their native disulfide bonds at redox conditions that are similar to the situation in the secretory vesicles in vivo and (ii) that the presen ce of protein disulfide isomerase does not overcome this problem. The resul ts indicate that the previously described thermodynamic disulfide exchange folding problem of IGF-I in vitro is also present in vivo. Speculatively, w e suggest that the thermodynamic disulfide exchange properties of IGF-I and II are biologically significant for inactivation of the unbound growth fac tors by disulfide exchange reactions to generate variants destined for rapi d clearance. (C) 1999 Federation of European Biochemical Societies.