The SOXE transcription factors—SOX8, SOX9 and SOX10—share a bi-partite transactivation mechanism
Year: 2019
Type: article
Abstract: SOX8, SOX9 and SOX10 compose the SOXE transcription factor group. They govern cell fate and differentiation in many lineages, and mutations impairing their activity cause severe diseases, including campomelic dysplasia (SOX9), sex determination disorders (SOX8 and SOX9) and Waardenburg-Shah syndrome (SOX10). However, incomplete knowledge of their modes of action limits disease understanding. We here uncover that the proteins share a bipartite transactivation mechanism, whereby a transactivation domain in the middle of the proteins (TAM) synergizes with a C-terminal one (TAC). TAM comprises amphipathic α-helices predicted to form a protein-binding pocket and overlapping with minimal transactivation motifs (9-aa-TAD) described in many transcription factors. One 9-aa-TAD sequence includes an evolutionarily conserved and functionally required EΦ[D/E]QYΦ motif. SOXF proteins (SOX7, SOX17 and SOX18) contain an identical motif, suggesting evolution from a common ancestor already harboring this motif, whereas TAC and other transactivating SOX proteins feature only remotely related motifs. Missense variants in this SOXE/SOXF-specific motif are rare in control individuals, but have been detected in cancers, supporting its importance in development and physiology. By deepening understanding of mechanisms underlying the central transactivation function of SOXE proteins, these findings should help further decipher molecular networks essential for development and health and dysregulated in diseases.
Source: Nucleic Acids Research
DOI: 10.1093/nar/gkz523
Authors: Abdul Haseeb, Véronique Lefebvre
Institution: Children's Hospital of Philadelphia
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,992
OpenAlex ID: W2949942382