类胰岛素生长因子-1何以折叠成2种高级结构的分子基础

Molecular Basis of Insulin-like Growth Factor-1 Folds into Two Structures

胰岛素和IGF-1属于同一超家族,具有共同的结构模体和非常类似的三维结构,但两者的折叠行为却迥然不同。胰岛素和单链胰岛素(PIP)折叠成唯一的热力学稳定的三维结构,而IGF-1则折叠成两种热力学稳定的三维结构。即是说:IGF-1的同一序列编码两种折叠信息。是序列中的什么部位决定胰岛素/PIP和IGF-1具有不同的折叠行为?这是一个极为有趣且长期为人们所困惑的问题。本实验室在PIP和mini-IGF-1工作的基础上,用蛋白质工程技术先后设计表达了一系列胰岛素和IGF-1的杂交分子,阐明了胰岛素和IGF-1不同折叠行为的分子基础。此外,还研究了文昌鱼胰岛素类似肽(aILP)的体外再折叠,结果提示胰岛素和IGF-1的不同折叠行为是由它们的祖先分子aILP分支进化而来的。

Insulin and Insulin-like Growth Factor - 1 （ IGF - 1 ） belong to the same super-family with common structure motif and very similar three-dimensional structure. But their folding behavior is quite different. Insulin/single - chain insulin （PIP） folds into a unique thermodynamically stable three - dimensional structure, while IGF - 1 folds into two thermody- namically stable three-dimensional structures. Which part of the molecules makes insulin/PIP and IGF - 1 possess different folding behavior？ This has been a very interesting but not well characterized problem for very long time in the field of protein folding. Based on the work of PIP and mini-IGF - 1, a series of hybrid molecules of insulin and IGF - 1 were designed and prepared by the means of protein engineering, by which the molecular basis of the different folding behavior of insulin and IGF - 1 has been revealed. In addition, the in vitro folding process of amphioxus insulin-like peptide （ aILP）, well recog- nized as the common ancestor molecular of insulin and IGF - 1, has been investigated, and suggesting that the different folding behavior of insulin and IGF - 1 was a bifurcating evolution from their ancestor molecular aILP.