Tracing the function expansion for a primordial protein fold in the era of fold-based function prediction: β-trefoil.

IF 2.9 3区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
PLoS ONE Pub Date : 2025-07-03 eCollection Date: 2025-01-01 DOI:10.1371/journal.pone.0320177
Moushmi Goswami, Subhashini Srinivasan
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引用次数: 0

Abstract

The incredibly narrow protein fold bottleneck, which separates the billions of unique proteins on one side to deliver diverse biological functions on the other, arises from folds that tolerate mutations during evolution. One such fold, called the β-trefoil, is present in functionally diverse proteins including cytokines involved in the immune system such as interleukin-1. The unrecognizable sequence-level diversity, even among paralogs of interleukin-1 within the same chromosomal locus, suggests the resilience of this fold to mutational onslaught. Furthermore, β-trefoil domain containing-proteins are known to coexist with other domains to achieve functional diversity. In this study, we challenge the reach and limitations of function prediction using fold-fold comparison using β-trefoil fold as an example. We identified proteins containing β-trefoil fold belonging to thirty-two distinct functional classes based on diverse domain architecture and/or functional annotation by mining both the PDB and AlphaFold databases using fold-fold comparison. Among the proteins with novel domain architecture we find β-trefoil along with chitinase, lipase, β-glucosidase, protein kinase, peptidoglycan-binding + peptidase matrixin, glycosyl hydrolases family 3 + PA14 + fibronectin type- III, alpha galactosidase A, PhoD-like phosphatase, insecticidal crystal toxin, trypsin, alginate lyase and two novel structurally uncharacterized domains. We demonstrate that fold-fold comparison can extend function prediction beyond the reach of sequence-based approach and provides an opportunity to discover novel domain architecture associated with known folds. However, since extending fold similarity to functional similarity may be challenged by convergent fold evolution, we explore if β-trefoil may be a convergent evolution and share our hypothesis.

在基于折叠的功能预测时代追踪原始蛋白质折叠的功能扩展:β-三叶草。
令人难以置信的狭窄的蛋白质折叠瓶颈,将数十亿独特的蛋白质分离在一边,以提供不同的生物功能,产生于进化过程中耐受突变的折叠。其中一种折叠被称为β-三叶草,存在于功能多样的蛋白质中,包括与免疫系统有关的细胞因子,如白细胞介素-1。无法识别的序列水平多样性,甚至在同一染色体位点的白介素-1的类似物中,表明这一折叠对突变冲击的弹性。此外,已知含有β-三叶结构域的蛋白质与其他结构域共存以实现功能多样性。在本研究中,我们以β-三叶折叠为例,挑战了折叠比较功能预测的范围和局限性。我们通过对PDB和AlphaFold数据库进行折叠比较,基于不同的结构域结构和/或功能注释,鉴定出含有β-三叶折叠的蛋白质属于32个不同的功能类。在具有新结构域的蛋白质中,我们发现了β-三叶草、几丁质酶、脂肪酶、β-葡萄糖苷酶、蛋白激酶、肽聚糖结合+肽酶基质蛋白、糖基水解酶家族3 + PA14 +纤维连接蛋白型- III、α -半乳糖苷酶A、phod样磷酸酶、杀虫晶体毒素、胰蛋白酶、海藻酸裂解酶和两个新的结构域。我们证明了折叠比较可以将功能预测扩展到基于序列的方法之外,并提供了一个发现与已知折叠相关的新领域架构的机会。然而,由于将褶皱相似性扩展到功能相似性可能受到收敛褶皱进化的挑战,我们探索β-三叶是否可能是一个收敛进化并分享我们的假设。
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
PLoS ONE
PLoS ONE 生物-生物学
CiteScore
6.20
自引率
5.40%
发文量
14242
审稿时长
3.7 months
期刊介绍: PLOS ONE is an international, peer-reviewed, open-access, online publication. PLOS ONE welcomes reports on primary research from any scientific discipline. It provides: * Open-access—freely accessible online, authors retain copyright * Fast publication times * Peer review by expert, practicing researchers * Post-publication tools to indicate quality and impact * Community-based dialogue on articles * Worldwide media coverage
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