Sologova Susanna S, Zavadskiy Sergey P, Mokhosoev Innokenty M, Moldogazieva Nurbubu T
Nelyubin Institute of Pharmacy, Sechenov First Moscow State Medical University, (Sechenov University), 119991 Moscow, Russia.
Department of Biochemistry and Molecular Biology, Pirogov Russian National Research Medical University, 117997 Moscow, Russia.
Metabolites. 2022 May 21;12(5):464. doi: 10.3390/metabo12050464.
Short linear motifs (SLiMs) are evolutionarily conserved functional modules of proteins that represent amino acid stretches composed of 3 to 10 residues. The biological activities of two short peptide segments of human alpha-fetoprotein (AFP), a major embryo-specific and cancer-related protein, have been confirmed experimentally. This is a heptapeptide segment LDSYQCT in domain I designated as AFP and a nonapeptide segment EMTPVNPGV in domain III designated as GIP-9. In our work, we searched the UniprotKB database for human proteins that contain SLiMs with sequence similarity to the both segments of human AFP and undertook gene ontology (GO)-based functional categorization of retrieved proteins. Gene set enrichment analysis included GO terms for biological process, molecular function, metabolic pathway, KEGG pathway, and protein-protein interaction (PPI) categories. We identified the SLiMs of interest in a variety of non-homologous proteins involved in multiple cellular processes underlying embryonic development, cancer progression, and, unexpectedly, the regulation of redox homeostasis. These included transcription factors, cell adhesion proteins, ubiquitin-activating and conjugating enzymes, cell signaling proteins, and oxidoreductase enzymes. They function by regulating cell proliferation and differentiation, cell cycle, DNA replication/repair/recombination, metabolism, immune/inflammatory response, and apoptosis. In addition to the retrieved genes, new interacting genes were identified. Our data support the hypothesis that conserved SLiMs are incorporated into non-homologous proteins to serve as functional blocks for their orchestrated functioning.
短线性基序（SLiMs）是蛋白质中进化保守的功能模块，代表由3至10个残基组成的氨基酸片段。人甲胎蛋白（AFP）是一种主要的胚胎特异性和癌症相关蛋白，其两个短肽段的生物学活性已通过实验得到证实。这是结构域I中名为AFP的七肽段LDSYQCT和结构域III中名为GIP-9的九肽段EMTPVNPGV。在我们的研究中，我们在UniprotKB数据库中搜索了含有与人类AFP两个片段具有序列相似性的SLiMs的人类蛋白质，并对检索到的蛋白质进行了基于基因本体（GO）的功能分类。基因集富集分析包括生物学过程、分子功能、代谢途径、KEGG途径和蛋白质-蛋白质相互作用（PPI）类别的GO术语。我们在多种非同源蛋白质中鉴定出了感兴趣的SLiMs，这些蛋白质参与了胚胎发育、癌症进展以及出乎意料的氧化还原稳态调节等多个细胞过程。其中包括转录因子、细胞粘附蛋白、泛素激活和缀合酶、细胞信号蛋白和氧化还原酶。它们通过调节细胞增殖和分化、细胞周期、DNA复制/修复/重组、代谢、免疫/炎症反应和细胞凋亡来发挥作用。除了检索到的基因外，还鉴定出了新的相互作用基因。我们的数据支持这样一种假设，即保守的SLiMs被纳入非同源蛋白质中，作为其协调功能的功能模块。
