Short Linear Motifs Orchestrate Functioning of Human Proteins during Embryonic Development, Redox Regulation, and Cancer

Abstract

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 AFP14–20 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.

Role of oxidative stress in the relationship between periodontitis and systemic diseases

“…The specificity of multiple amino acids to undergo carbonylation has made this modification a widely used biomarker for assessing oxidative damage to proteins ( Caliri et al, 2021 ). Reversible oxidation of proteins with adjacent cysteine residues, possibly including protein kinases and phosphatases, can regulate protein function and redox signaling pathways in various stress responses ( Caliri et al, 2021 ; Sologova et al, 2022 ).…”

Short Linear Motifs in Colorectal Cancer Interactome and Tumorigenesis

“…Cooperation does not require physical contact between the linear motifs and usually depends on two (or more) moderate affinity contacts that synergize to produce a greater effective affinity in the interaction [ 11 ]. A significant challenge in SLiM characterization is that, despite their stability in various proteins, SLiMs can show multiple three-dimensional structures [ 20 , 21 ]. In native proteins, SLiMs are intertwined and overlapped to act as functional units.…”

“…This variety of structural conformations for a single sequence explains why the same unit is sometimes observed in numerous unrelated non-homologous proteins. As a result, proteins may have similar functions despite showing widely different amino acid sequences and three-dimensional structures [ 21 ]. On the other hand, the majority of protein domains maintain distinct patterns of amino acid conservation, indicating that they can bind SLiMs with high intrinsic specificity, thereby modulating PPIs [ 22 ].…”

“…In particular, the AFP C-terminal SLiM E 489 MTPVNPGV 497 can inhibit mouse uterine cell proliferation and has shown anticancer effects in MCF-7 breast cancer cells [ 30 ]. In addition, local alignment analysis revealed high similarity between this AFP C-terminal SLiM and AXIN 2, a protein involved in the WNT pathway, which is deregulated in CRC and hepatocellular carcinoma [ 21 , 32 ]. In addition, the N-terminal heptapeptide of AFP (AFP14-20) interacts with the consensus motif (CxxGY/FxGx) of EGF family proteins, including the well-known cancer-related factor EGF [ 33 ].…”