Cumulative phylogenetic, sequence and structural analysis of Insulin superfamily proteins provide unique structure-function insights.

IF 2.8 4区 医学 Q3 CHEMISTRY, MEDICINAL
Molecular Informatics Pub Date : 2024-09-01 Epub Date: 2024-07-08 DOI:10.1002/minf.202300160
Shrilakshmi Sheshagiri Rao, Shankar V Kundapura, Debayan Dey, Chandrasekaran Palaniappan, Kanagaraj Sekar, Ananda Kulal, Udupi A Ramagopal
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引用次数: 0

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.

对胰岛素超家族蛋白的系统发育、序列和结构的累积分析提供了独特的结构-功能见解。
胰岛素超家族蛋白(ISPs),特别是胰岛素、IGFs 和松弛素蛋白是动物生理的关键调节因子。众所周知,它们是由同一祖先基因进化而来,并分化成具有不同序列和不同功能的蛋白质,但通过高度保守的二硫键保持着相似的结构。最近,这些蛋白质的序列数据和结构激增,促使人们需要根据现有的功能和结构信息(包括 ISP 与其同源受体的代表性复合结构),对这些序列(427 个序列)的进化进行全面分析。这项研究揭示了:(a) IGFs 的序列保存率异常之高(184 个序列的保存率大于 90%),并为如此高的序列保存率提供了一个可能的基于结构的理由;(b) 为功能多样的弛缓素家族成员的受体结合标志图案提供了一个最新的定义;(c) 在一些胰岛素序列中提供了一个可能的非经典 C 肽裂解位点。IGFs 的高度保守性似乎代表了一种典型的情况,即通过与多个伙伴的重要生理相互作用来抵抗序列多样性。我们还提出了几个不同的胰岛素序列中 C 肽裂解的可能机制,并重新定义了松弛素家族的受体结合特征基团。最后,我们从分子动力学模拟支持下在其他胰岛素超家族蛋白成员中观察到的伴随变化中得到启发,为具有潜在治疗用途的最小修饰胰岛素突变体提供了基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular Informatics
Molecular Informatics CHEMISTRY, MEDICINAL-MATHEMATICAL & COMPUTATIONAL BIOLOGY
CiteScore
7.30
自引率
2.80%
发文量
70
审稿时长
3 months
期刊介绍: Molecular Informatics is a peer-reviewed, international forum for publication of high-quality, interdisciplinary research on all molecular aspects of bio/cheminformatics and computer-assisted molecular design. Molecular Informatics succeeded QSAR & Combinatorial Science in 2010. Molecular Informatics presents methodological innovations that will lead to a deeper understanding of ligand-receptor interactions, macromolecular complexes, molecular networks, design concepts and processes that demonstrate how ideas and design concepts lead to molecules with a desired structure or function, preferably including experimental validation. The journal''s scope includes but is not limited to the fields of drug discovery and chemical biology, protein and nucleic acid engineering and design, the design of nanomolecular structures, strategies for modeling of macromolecular assemblies, molecular networks and systems, pharmaco- and chemogenomics, computer-assisted screening strategies, as well as novel technologies for the de novo design of biologically active molecules. As a unique feature Molecular Informatics publishes so-called "Methods Corner" review-type articles which feature important technological concepts and advances within the scope of the journal.
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