Abstract：
The insulin superfamily proteins (ISPs), in particular, insulin, IGFs and relaxin proteins are key modulators of animal physiology. They are known to have evolved from the same ancestral gene and have diverged into proteins with varied sequences and distinct functions, but maintain a similar structural architecture stabilized by highly conserved disulphide bridges. The recent surge of sequence data and the structures of these proteins prompted a need for a comprehensive analysis, which connects the evolution of these sequences (427 sequences) in the light of available functional and structural information including representative complex structures of ISPs with their cognate receptors. This study reveals (a) unusually high sequence conservation of IGFs (>90 % conservation in 184 sequences) and provides a possible structure-based rationale for such high sequence conservation; (b) provides an updated definition of the receptor-binding signature motif of the functionally diverse relaxin family members (c) provides a probable non-canonical C-peptide cleavage site in a few insulin sequences. The high conservation of IGFs appears to represent a classic case of resistance to sequence diversity exerted by physiologically important interactions with multiple partners. We also propose a probable mechanism for C-peptide cleavage in a few distinct insulin sequences and redefine the receptor-binding signature motif of the relaxin family. Lastly, we provide a basis for minimally modified insulin mutants with potential therapeutic application, inspired by concomitant changes observed in other insulin superfamily protein members supported by molecular dynamics simulation.
摘要：
胰岛素超家族蛋白（ISP），特别是,胰岛素，IGF和松弛素蛋白是动物生理学的关键调节剂。已知它们是从相同的祖先基因进化而来的，并分化为具有不同序列和不同功能的蛋白质，但保持高度保守的二硫桥稳定的类似结构架构。最近的序列数据和这些蛋白质的结构激增，促使人们需要进行全面分析，根据可用的功能和结构信息，包括ISP的代表性复杂结构及其同源受体，将这些序列（427序列）的进化联系起来。该研究揭示了(a)IGFs异常高的序列保守性(在184个序列中保守性>90%),并为这种高序列保守性提供了可能的基于结构的基本原理;(b)提供了功能多样的松弛素家族成员的受体结合特征基序的更新定义;(c)在一些胰岛素序列中提供了可能的非常规C肽切割位点。IGFs的高度保守性似乎代表了对与多个伴侣的生理重要相互作用所产生的序列多样性的抵抗的经典案例。我们还提出了在一些不同的胰岛素序列中切割C肽的可能机制，并重新定义了松弛素家族的受体结合特征基序。最后,我们为具有潜在治疗应用的最小修饰胰岛素突变体提供了基础，受分子动力学模拟支持的其他胰岛素超家族蛋白成员中观察到的伴随变化的启发。
