Molecular evolution guided functional analyses reveals Nucleobindin-1 as a canonical E-box binding protein promoting Epithelial-to-Mesenchymal transition (EMT).

Calcium binding proteins (CBPs) function in response to changes in intracellular calcium (Ca²⁺) levels by modulating intracellular signaling pathways. Calcium sensors, including Nucleobindins (Nucb1/2) undergo Ca²⁺-binding induced conformational changes and bind to target proteins. Nucleobindins possess additional uncharacterized domains including partly characterized EF-hands. We study the molecular evolution of Nucleobindins in eukaryotes emphasizing on the N-terminal DNA binding domain (DBD) that emerged as a result of domain insertion event in Nucb1/2 domain-scaffold in an ancestor to the opisthokonts. Our results from in silico analyses and functional assays revealed that DBD of Nucb1 binds to canonical E-box sequences and triggers cell epithelial-mesenchymal transition (EMT). Thus, post gene duplication, Nucb1 has emerged as unconventional Ca²⁺-binding transcriptional regulators that can induce EMT.

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