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. 2017 Sep;24(9):1540-1547.
doi: 10.1038/cdd.2017.76. Epub 2017 Jun 16.

Structural basis for the regulatory interactions of proapoptotic Par-4

Udaya K Tiruttani Subhramanyam  1   2 , Jan Kubicek  2   3 , Ulf B Eidhoff  2 , Joerg Labahn  1   2
Affiliations

Structural basis for the regulatory interactions of proapoptotic Par-4

Udaya K Tiruttani Subhramanyam et al. Cell Death Differ. 2017 Sep.

Abstract

Par-4 is a unique proapoptotic protein with the ability to induce apoptosis selectively in cancer cells. The X-ray crystal structure of the C-terminal domain of Par-4 (Par-4CC), which regulates its apoptotic function, was obtained by MAD phasing. Par-4 homodimerizes by forming a parallel coiled-coil structure. The N-terminal half of Par-4CC contains the homodimerization subdomain. This structure includes a nuclear export signal (Par-4NES) sequence, which is masked upon dimerization indicating a potential mechanism for nuclear localization. The heteromeric-interaction models specifically showed that charge interaction is an important factor in the stability of heteromers of the C-terminal leucine zipper subdomain of Par-4 (Par-4LZ). These heteromer models also displayed NES masking capacity and therefore the ability to influence intracellular localization.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Asymmetric unit of the Par-4CC crystal. Representation of the asymmetric unit of the SeMet-labeled Par-4CC crystal. The asymmetric unit contains seven molecules, which are shown with different colors. Each of them forms homodimeric coiled-coil structures. Chain E forms a crystallographic homodimer with a symmetry equivalent molecule
Figure 2
Figure 2
Homodimeric interactions of Par-4CC. (a) Structure-based heptad register of the protein sequence of Par-4CC as assigned by the SOCKET program. Double-headed arrows depict salt bridges: intrahelical salt bridge (black) and interhelical salt bridge (magenta). The red double-headed arrow represents the interhelical charge repulsion. Sequence numbering is as per the UniProt id: Q62627. The region of Par-4CC corresponding to the homodimerization and leucine zippers domains are depicted. (b) Chain representation of the crystal structure of the two domains of the homodimeric coiled-coil of Par-4CC: homodimerization domain (left) and leucine zipper domain (right). Side chains of the residues occupying the coiled-coil interface are shown in crimson color for chain A (ice blue) and cyan for chain B (gold). The interhelical and intrahelical salt bridges are depicted. For clarity only one set of residues involved in salt-bridge formation are shown with their side chains in atom-type representation. Asparagines (blue) occupying the heptad positions a in both the domains, and the residues at every heptad positions d of the leucine zipper domain are labeled. Electron density (2mFo-DFc type) is contoured at 1.0σ. See also Supplementary Table S1
Figure 3
Figure 3
Structure of Par-4NES. Structure of predicted NES of Par-4CC. Electron density map of 2mFo-DFc type contoured at 0.8σ is shown. See also Supplementary Table S1
Figure 4
Figure 4
Par-4 coiled-coil interactions with binding partners. Left to right, surface representations of the crystal structure of homodimeric coiled-coil Par-4CC and its heterodimeric-interaction models with THAP1, AATF, Amida and DAPK3 (dashed box). Model surfaces are colored by electrostatic potential (ESP) on a sliding scale from blue (positive) to red (negative). For heterodimeric-interaction models, ESP surfaces are shown only for interacting regions. The black double-headed arrow in the Par-4CC homodimer represents the charge repulsion between Asp305 and Glu310′. Regions corresponding to the Par-4CC charge repulsion and Par-4NES are depicted with dashed lines in the heterodimeric-interaction models. Salt bridges are listed: underlined are the residues that show repulsion in Par-4CC homodimer. See also Supplementary Figure S3 and Supplementary Table S2
Figure 5
Figure 5
Model of the Par-4-DAPK3 complex. Left, the homodimeric model of Par-4. Middle, homodimeric model of DAPK3 with kinase domain, predicted coiled-coil region (CC) and C-terminal LZ motif acting as dimerization domain. Right, suggested complex of Par-4 and DAPK3 where an active DAPK3 with its CC is bound to the LZ motif of Par-4 and its kinase domain is reaching out to the SAC domain of Par-4 to phosphorylate the Thr155 residue
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