Evolutionary Conserved Short Linear Motifs Provide Insights into the Cellular Response to Stress

HIGHLIGHTS: 1. Hundreds of short linear motifs (SLiMs) that exhibit a high degree of sequence similarity to two biologically active sites of human alpha-fetoprotein (AFP) were identified. 2. The SLiMs of interest are ubiquitously distributed and found in proteins of both eukaryotic and prokaryotic species. 3. Proteins retrieved by sequence alignment belonged to various functional classes to be directly or indirectly involved in cellular response to stress. 4. Our findings provide insights into the common functions of evolutionary conserved SLiMs and putative involvement of AFP in response to external and internal stimuli during cellular adaptation during embryonic development and cancer. ABSTRACT: Short linear motifs (SLiMs) are evolutionarily conserved functional modules of proteins composed of 3 to 10 residues and involved in multiple cellular functions. Here, we performed a search for SLiMs that exert sequence similarity to two segments of alpha-fetoprotein (AFP), a major mammalian embryonic and cancer-associated protein. Biological activities of the peptides, LDSYQCT (AFP(14–20)) and EMTPVNPGV (GIP-9), have been previously confirmed under in vitro and in vivo conditions. In our study, we retrieved a vast array of proteins that contain SLiMs of interest from both prokaryotic and eukaryotic species, including viruses, bacteria, archaea, invertebrates, and vertebrates. Comprehensive Gene Ontology enrichment analysis showed that proteins from multiple functional classes, including enzymes, transcription factors, as well as those involved in signaling, cell cycle, and quality control, and ribosomal proteins were implicated in cellular adaptation to environmental stress conditions. These include response to oxidative and metabolic stress, hypoxia, DNA and RNA damage, protein degradation, as well as antimicrobial, antiviral, and immune response. Thus, our data enabled insights into the common functions of SLiMs evolutionary conserved across all taxonomic categories. These SLiMs can serve as important players in cellular adaptation to stress, which is crucial for cell functioning.