A novel heterodimerization domain, CRM1, and 14-3-3 control subcellular localization of the MondoA-Mlx heterocomplex.
Among members of the bHLHZip family of transcriptional regulators, MondoA and Mlx have the unique property of cytoplasmic localization. We have proposed that MondoA-Mlx heterodimers accumulate in the nucleus in response to extracellular cues. Our previous work implicated heterodimerization between MondoA and Mlx and a conserved domain in the N ... terminus of MondoA as important determinants of MondoA-Mlx subcellular localization. MondoA and Mlx share sequence similarity in their bHLHZip domains and C termini. Here we show that for both MondoA and Mlx, this C-terminal domain has cytoplasmic localization activity that is required by the protein monomers to accumulate in the cytoplasm. This C-terminal domain is also a novel dimerization interface that functions independently of the leucine zipper to mediate heterotypic interactions between MondoA and Mlx. Dimerization between MondoA and Mlx inactivates the cytoplasmic localization activity of their C termini and is necessary for the heterocomplex to accumulate in the nucleus. MondoA-Mlx heterodimers, while poised for nuclear entry, are retained in the cytoplasm by conserved domains in the N terminus of MondoA. Mondo conserved regions (MCRs) II and III contribute to cytoplasmic localization of MondoA-Mlx by functioning as a CRM1-dependent nuclear export signal and as a novel binding site for 14-3-3 family members, respectively. We propose that the nuclear accumulation of MondoA and Mlx is a two-step process. First, heterodimerization abolishes the cytoplasmic localization activity of their C termini. Second, an extracellular signal(s) must overcome the cytoplasmic localization function imparted by CRM1 and 14-3-3 binding to the N terminus of MondoA.
Mesh Terms:
14-3-3 Proteins, 3T3 Cells, Active Transport, Cell Nucleus, Amino Acid Sequence, Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Cell Nucleus, Cytoplasm, DNA-Binding Proteins, Dimerization, Genes, Reporter, Helix-Loop-Helix Motifs, Humans, Leucine Zippers, Macromolecular Substances, Mice, Molecular Sequence Data, Nuclear Localization Signals, Nuclear Proteins, Protein Structure, Tertiary, Recombinant Fusion Proteins, Sequence Alignment, Transcription Factors, Two-Hybrid System Techniques, Tyrosine 3-Monooxygenase
14-3-3 Proteins, 3T3 Cells, Active Transport, Cell Nucleus, Amino Acid Sequence, Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Cell Nucleus, Cytoplasm, DNA-Binding Proteins, Dimerization, Genes, Reporter, Helix-Loop-Helix Motifs, Humans, Leucine Zippers, Macromolecular Substances, Mice, Molecular Sequence Data, Nuclear Localization Signals, Nuclear Proteins, Protein Structure, Tertiary, Recombinant Fusion Proteins, Sequence Alignment, Transcription Factors, Two-Hybrid System Techniques, Tyrosine 3-Monooxygenase
Mol. Cell. Biol.
Date: Dec. 01, 2002
PubMed ID: 12446771
View in: Pubmed Google Scholar
Download Curated Data For This Publication
10314
Switch View:
- Interactions 7