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PMID:12446771
| Citation |
Eilers, AL, Sundwall, E, Lin, M, Sullivan, AA and Ayer, DE (2002) A novel heterodimerization domain, CRM1, and 14-3-3 control subcellular localization of the MondoA-Mlx heterocomplex. Mol. Cell. Biol. 22:8514-26 |
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| Abstract |
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. |
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| Keywords |
14-3-3 Proteins; 3T3 Cells; Active Transport, Cell Nucleus/physiology; Amino Acid Sequence; Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Cell Nucleus/metabolism; Cytoplasm/metabolism; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Dimerization; Genes, Reporter; Helix-Loop-Helix Motifs; Humans; Leucine Zippers; Macromolecular Substances; Mice; Molecular Sequence Data; Nuclear Localization Signals; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Protein Structure, Tertiary; Recombinant Fusion Proteins/genetics; Recombinant Fusion Proteins/metabolism; Sequence Alignment; Transcription Factors/genetics; Transcription Factors/metabolism; Two-Hybrid System Techniques; Tyrosine 3-Monooxygenase/metabolism |
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Significance
Annotations
| Gene product | Qualifier | GO ID | GO term name | Evidence Code | with/from | Aspect | Notes | Status |
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