Structural and Mechanistic Basis for Nucleocytoplasmic Shuttling of SOX Transcription Factors

SRY-related HMG-box (SOX) proteins are transcriptional regulators that play indispensable roles in a range of organogenesis pathways. They act as ‘master’ switches in embryonic development and drive cell differentiation. Reflecting their central role in development, mutations lead to diseases such as cancer and autoimmune disorders. In order for SOX proteins to perform their role as transcription factors, they must first be transported to the nucleus. Disruption of this nuclear import process has been demonstrated to cause a range of diseases, including genetic sex reversal, leukaemia, melanoma, and multiple cancers. This study investigates the nuclear localization of the SOX proteins, with a specific focus on receptor-binding specificity. This approach utilises recombinant protein expression, purification, and high-resolution structural techniques, including X-ray crystallography and CryoEM. Structural determination of these complexes provides critical binding determinants at the interface of SOX factors and nuclear import receptors, providing new insights into receptor and tissue-specific nuclear import of the SOX proteins. Overall, the project establishes a structural and molecular basis for the cellular localization of SOX proteins and underlying diseases resulting from mislocalization.