| Abstract
| - Insulin and insulin-like growth factor 1 (IGF-1) share high sequence homology, but their foldingbehaviors are significantly different: insulin folds into one unique thermodynamically controlled structure,while IGF-1 folds into two thermodynamically controlled disulfide isomers. However, the origin of theirdifferent folding behaviors is still elusive. The amphioxus insulin-like peptide (ILP) is thought to be thecommon ancestor of insulin and IGF-1. A recombinant single-chain ILP has been expressed previously,and now its folding behavior is investigated. The folding behavior of ILP shows the characteristics ofboth insulin and IGF-1. On one hand, two thermodynamically controlled disulfide isomers of ILP havebeen identified; on the other hand, the content of isomer 1 (its disulfides are deduced identical to thoseof swap IGF-1) is much less than that of isomer 2 (its disulfides are deduced identical to those of nativeIGF-1); that is, more than 96% of ILP folds into the native structure. The present results suggest that thedifferent folding behaviors of insulin and IGF-1 are acquired through a bifurcating evolution: the tendencyof forming the thermodynamically controlled non-native disulfide isomer is diminished during evolutionfrom ILP to insulin, while this tendency is amplified during evolution from ILP to IGF-1. Moreover, theN-terminal Gln residue of ILP can spontaneously form a pyroglutamate residue, and its cyclization has asignificant effect on the folding behavior of ILP: the percentage of isomer 1 is approximately 2-fold thatof isomer 1 of the noncyclized ILP; that is, isomer 1 becomes more favored when the N-terminal residueof ILP is cyclized. So, we deduce that the N-terminal residues have a significant effect on the foldingproperties of insulin, IGF-1, and ILP.
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