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The crystal structure of the non-liganded 14-3-3sigma protein: insights into determinants of isoform specific ligand
Anne Benzinger1, Grzegorz M Popowicz, Joma K Joy
1Molecular Oncology Group, Max-Planck-Institute for Biochemistry, Martinsried, Germany.
Abstract:
Seven different, but highly conserved 14-3-3 proteins are involved in diverse signaling pathways in human cells. It is unclear how the 14-3-3sigma isoform, a transcriptional target of p53, exerts its inhibitory effect on the cell cycle in the presence of other 14-3-3 isoforms, which are constitutively expressed at high levels. In order to identify structural differences between the 14-3-3 isoforms, we solved the crystal structure of the human 14-3-3sigma protein at a resolution of 2.8 Angstroms and compared it to the known structures of 14-3-3zeta and 14-3-3tau. The global architecture of the 14-3-3sigma fold is similar to the previously determined structures of 14-3-3zeta and 14-3-3t: two 14-3-3sigma molecules form a cup-shaped dimer. Significant differences between these 14-3-3 isoforms were detected adjacent to the amphipathic groove, which mediates the binding to phosphorylated consensus motifs in 14-3-3-ligands. Another specificity determining region is localized between amino-acids 203 to 215. These differences presumably select for the interaction with specific ligands, which may explain the different biological functions of the respective 14-3-3 isoforms. Furthermore, the two 14-3-3sigma molecules forming a dimer differ by the spatial position of the ninth helix, which is shifted to the inside of the ligand interaction surface, thus indicating adaptability of this part of the molecule. In addition, 5 non-conserved residues are located at the interface between two 14-3-3sigma proteins forming a dimer and represent candidate determinants of homo- and hetero-dimerization specificity. The structural differences among the 14-3-3 isoforms described here presumably contribute to isoform-specific interactions and functions.
Insights
Structural differences in 14-3-3 proteins, particularly 14-3-3sigma, were identified using crystal structures. These variations, especially near ligand-binding sites and dimer interfaces, likely explain isoform-specific functions in cell signaling.
Area of Science:
- Molecular Biology
- Structural Biology
- Cell Signaling
Background:
- Seven highly conserved 14-3-3 proteins regulate diverse human cell signaling pathways.
- The specific inhibitory role of 14-3-3sigma in cell cycle regulation, despite high constitutive expression of other isoforms, remains unclear.
- Understanding structural basis for isoform-specific functions is crucial for deciphering 14-3-3 protein roles.
Purpose of the Study:
- To identify structural differences between human 14-3-3 isoforms, focusing on 14-3-3sigma.
- To elucidate how structural variations contribute to isoform-specific ligand interactions and biological functions.
Main Methods:
- Crystal structure determination of human 14-3-3sigma protein at 2.8 Angstrom resolution.
- Comparative structural analysis of 14-3-3sigma against known structures of 14-3-3zeta and 14-3-3tau.
Main Results:
- 14-3-3sigma forms a cup-shaped dimer, similar to other isoforms, but exhibits significant structural differences near the ligand-binding amphipathic groove.
- A distinct specificity-determining region between amino acids 203-215 and variations in the ninth helix position within the dimer interface were identified.
- Five non-conserved residues at the dimer interface suggest roles in homo- and hetero-dimerization specificity.
Conclusions:
- Structural disparities among 14-3-3 isoforms, particularly in ligand interaction regions and dimer interfaces, are key determinants of their specific functions.
- These findings provide a structural basis for understanding the distinct biological roles of individual 14-3-3 proteins in cellular signaling.
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