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

Biochim Biophys Acta Proteins Proteom. 2019 Sep;1867(9):765-775. doi: 10.1016/j.bbapap.2019.05.009. Epub 2019 Jun 6.

Abstract

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.

Keywords: DNA binding domain (DBD); E-box binding protein; Nucleobindins (Nucb1/2); Oncogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium-Binding Proteins* / genetics
  • Calcium-Binding Proteins* / metabolism
  • Computer Simulation*
  • DNA-Binding Proteins* / genetics
  • DNA-Binding Proteins* / metabolism
  • Epithelial-Mesenchymal Transition*
  • Evolution, Molecular*
  • Gene Duplication*
  • HEK293 Cells
  • Humans
  • MCF-7 Cells
  • Nerve Tissue Proteins* / genetics
  • Nerve Tissue Proteins* / metabolism
  • Nucleobindins
  • Protein Conformation
  • Protein Domains

Substances

  • Calcium-Binding Proteins
  • DNA-Binding Proteins
  • NUCB1 protein, human
  • Nerve Tissue Proteins
  • Nucleobindins