Inter-subunit crosstalk via PDZ synergistically governs allosteric activation of proapoptotic HtrA2

The mitochondrial serine protease High-temperature requirement A2 (HtrA2) is associated with various dis-eases including neurodegenerative disorders and cancer. Despite availability of structural details, the reports on HtrA2's mechanistic regulation that varies with the type of activation signals still remain non-concordant. To expound the role of regulatory PDZ (Postsynaptic density-95/Discs large/Zonula occludens-1) domains in multimodal activation of HtrA2, we generated heterotrimeric HtrA2 variants comprising different numbers of PDZs and/or active-site mutations. Sequential deletion of PDZs from the trimeric ensemble significantly affected its residual activity in a way that proffered a hypothesis advocating inter-molecular allosteric cross-talk via PDZs in HtrA2. Furthermore, structural and computational snapshots affirmed the role of PDZs in secondary structural element formation around the regulatory loops and coordinated reorganization of the N-terminal region. Therefore, apart from providing cues for devising structure-guided therapeutic strategies, this study establishes a physiologically relevant working model of complex allosteric regulation through a trans-mediated shared landscape.

Automated summary

The study demonstrates the importance of PDZ domains in the multimodal activation of HtrA2 through the generation of HtrA2 variants with different numbers of PDZs and/or active-site mutations. The study proposes a hypothesis on inter-molecular allosteric cross-talk via PDZs in HtrA2. Structural and computational snapshots also support the role of PDZs in the formation of secondary structural elements and the reorganization of the N-terminal region.