Posttranslational Modifications in Conserved Transcription Factors: A Survey of the TALE-Homeodomain Superclass in Human and Mouse

Abstract

Transcription factors (TFs) guide effector proteins like chromatin-modifying or -remodeling enzymes to distinct sites in the genome and thereby fulfill important early steps in translating the genome's sequence information into the production of proteins or functional RNAs. TFs of the same family are often highly conserved in evolution, raising the question of how proteins with seemingly similar structure and DNA-binding properties can exert physiologically distinct functions or respond to context-specific extracellular cues. A good example is the TALE superclass of homeodomain-containing proteins. All TALE-homeodomain proteins share a characteristic, 63-amino acid long homeodomain and bind to similar sequence motifs. Yet, they frequently fulfill non-redundant functions even in domains of co-expression and are subject to regulation by different signaling pathways. Here we provide an overview of posttranslational modifications that are associated with murine and human TALE-homeodomain proteins and discuss their possible importance for the biology of these TFs.

Keywords: IRX; MEIS; PBX; PREP/PKNOX; PTM; TGIF; homeodomain protein; protein phosphorylation.

FIGURE 1

Structure of TALE-HD proteins and examples of abundant, class-specific PTMs. (A) Comparison of the amino acid sequence of mouse TALE-HD domains. Helices 1–3 are highlighted in blue, the name-giving TALE-motif in red. (B) Domain structure of the five TALE-HD protein classes. The HD is shown as gray cylinder, conserved protein domains outside the HD in blue; nuclear export signal (NES): green; nuclear localization signal (NLS): orange. See text for details. Domain sizes are not drawn to scale. (C–E) PTM comparison among paralogs and between human and mouse orthologs. (C) Lysine-ubiquitination and serine-, threonine- and tyrosine-phosphorylation C-terminal to the HD in PBC class proteins. (D) Serine-phosphorylation in PBC class proteins N-terminal to the HD. (E) Arginine-methylation, lysine-ubiquitination and serine/threonine-phosphorylation in MEINOX-proteins. (F) Ubiquitination and phosphorylation in TGIF-class proteins. Numeration of modified amino acids in reference proteins is shown below each amino acid alignment. Color code: green: phosphorylation, blue: methylation, pink: ubiquitination; dark shades indicate PTMs, bright shades indicate residue conservation. A list of PTMs assessed in PBC, MEIS/PREP and TGIF as well as PTMs detected in IRO and MKX can be found in Table 1.