Folding of insulin-like growth factor I is thermodynamically controlled by insulin-like growth factor binding protein.
Insulin-like growth factor I (IGF-I) is thermodynamically unable to quantitatively form its native disulfides under reversible redox conditions in vitro [Hober et al. (1992) Biochemistry 31, 1749-1756]. These results prompted the question of how IGF-I may overcome this energetic problem in its folding in vivo. Here, we report that an IGF-I precursor, IGF-I-Ea, shows disulfide-exchange folding properties similar to those of mature IGF-I and, thus, is concluded not to overcome the identified folding problem of mature IGF-I. However, correct disulfide bonds are formed very efficiently when insulin-like growth factor binding protein 1 is added in equimolar amounts to IGF-I to the refolding mixture. On the basis of these results, we propose that one important function of at least one of the six homologous insulin-like growth factor binding proteins is to assist in the formation and maintenance of the native disulfides of IGF-I. To our knowledge, this is the first example where the folding of a mammalian protein or peptide in circulation has been demonstrated to be thermodynamically controlled by its binding protein. Speculatively, this could provide a mechanism to regulate the half-life of IGF-I in vivo by altering the interaction with insulin-like growth factor binding proteins.
Hober
S
S
BioScience Center, Pharmacia AB, Stockholm, Sweden.
Hansson
A
A
Uhlén
M
M
Nilsson
B
B
D002352:Carrier Proteins / Q000378:metabolism*; D004220:Disulfides / Q000737:chemistry; D018970:Insulin-Like Growth Factor Binding Protein 1; D007334:Insulin-Like Growth Factor I / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D011498:Protein Precursors / Q000737:chemistry; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D013816:Thermodynamics
D002352:Carrier Proteins; D004220:Disulfides; D018970:Insulin-Like Growth Factor Binding Protein 1; D011498:Protein Precursors; D011993:Recombinant Fusion Proteins; D007334:Insulin-Like Growth Factor I