The regulatory proteome

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For a living cell to function in its environment a large number of regulatory processes are needed, including regulation of cell proliferation, cell differentiation and cell death. The underlying mechanisms include regulation of gene expression, as well as, different post-translational modifications that regulate for example activity, stability, localization or degradation of the protein. An important class of regulatory proteins is transcription factors that determine when genes are switched on and off. About 1500 human transcription factors are known and these proteins are often expressed in a differential manner in different parts of the human body.

Regulation of gene expression

Transcription factors are regulatory proteins, and they are considered to be the most diverse and important mechanism of gene regulation. They constitute a large group of proteins with 1499 human genes coding for transcription factors found in the TF class database and with data in both the UniProt and Ensembl databases. They have DNA-binding domains that bind, specifically and with extreme affinity, to consensus DNA sequences and thereby activate (or in rare cases inhibit) transcription of DNA. Transcription factors are classified into families either based on the highly conserved sequences of the DNA binding domains, or on their three-dimensional protein structure. These structural motifs result in their specificity for the consensus sequence and the major classes include 778 proteins with zinc-coordinating DNA-binding domains (zinc-finger proteins), 173 proteins with basic domains (helix-loop-helix and leucine-zipper factors), and 395 proteins with helix-turn-helix domains (homeodomain factors). In Table 1, the transcription factors are classified according to structural motif as in the TFclass database.

Table 1. Structural classification of transcription factors.

Examples of transcription factors from different structural classes

The zinc-finger is a structural motif in which one or more zinc ions stabilize the protein fold as exemplified by the schematic representation of the estrogen receptor ESR1 (purple with zinc-ions in red) binding to DNA. ESR1 is a nuclear hormone receptor, here shown to be expressed in glandular cells and cells in endometrial stroma of the uterus by staining with the antibody CAB000037.

The structural motif known as the leucine-zipper consists of a leucine repeat region, which forms an alpha helix with a hydrophobic region responsible for dimerization. Here exemplified by a schematic representation of the proto-oncogene JUN (purple) binding as a homodimer to DNA.

JUN is a basic leucine-zipper factor, here shown to be expressed in glandular cells of the colon by immunohistochemical staining using the antibody CAB007780.

The helix-turn-helix motif is a DNA binding motif composed of two α-helices, which make contacts with DNA and are joined by a short turn. The schematic representation shows the transcription factor GBX1 (purple) binding to DNA. GBX1 is a homeo-domain factor, here shown to be expressed in follicle cells of the ovary using the antibody HPA055783.

Post-translational modifications of proteins

Post-translational modifications (PTM) are chemical modifications such as phosphorylation, glycosylation, ubiquitination, nitrosylation, methylation, acetylation, lipidation and proteolysis, which regulate activity, stability, localization and interaction of proteins. Most modifications are mediated by enzymes, which add or remove functional groups, proteins, lipids or sugars to or from amino acid side chains or cleave peptide bonds to remove specific sequences or subunits.

Phosphorylation

Phosphorylation is one of the most important post-translational modifications and plays a critical role in regulation of cell cycle, growth and differentiation, apoptosis and signal transduction pathways. It is a reversible process involving phosphorylation and dephosphorylation of a variety of substrates including proteins, lipids and carbohydrates. Protein activity and function are commonly regulated by phosphorylation on serine, threonine or tyrosine residues, which functions either by inducing conformational changes that regulate the catalytic activity or by recruiting other proteins that bind and recognize phosphomotifs. Kinases are the proteins mediating phosphorylation, and this large group of enzymes includes 501 predicted human genes.

TSSK1B is a serine/threonine-protein kinase required during spermatid development, here shown to be expressed in mature sperm in epididymis and in testis. The protein expression is visualised by immunohistochemistry using the antibody HPA027827.

Relevant links and publications

Uhlén M et al, 2015. Tissue-based map of the human proteome. Science
PubMed: 25613900 DOI: 10.1126/science.1260419