Allosteric Regulation of Serine Protease HtrA2 through Novel Non-Canonical Substrate Binding Pocket

Allosteric Regulation of Serine Protease HtrA2 through Novel Non-Canonical Substrate Binding Pocket

HtrA2, a trimeric proapoptotic serine protease is involved in several diseases including cancer and neurodegenerative disorders. Its unique ability to mediate apoptosis via multiple pathways makes it an important therapeutic target. In HtrA2, C-terminal PDZ domain upon substrate binding regulates its functions through coordinated conformational changes the mechanism of which is yet to be elucid...

Akt attenuation of the serine protease activity of HtrA2/Omi through phosphorylation of serine 212.

The serine protease HtrA2/Omi is released from the mitochondria into the cytosol following apoptosis stimuli, leading to the programmed cell death in caspase-dependent and -independent manners. The function of HtrA2/Omi closely relates to its protease activity, which is required for cleavage of its substrate such as the members of the X-linked inhibitor of apoptotic protein family. However, the...

Occupational hazards: allosteric regulation of protein kinases through the nucleotide-binding pocket.

Targeting the protein kinase ATP-binding pocket provides a significant opportunity for the treatment of disease. Recent studies have revealed a central activity-independent role for nucleotide pocket occupation in the allosteric behaviour of diverse kinases. Regulation of nucleotide pocket conformation with either nucleotides or ATP competitive inhibitors has revealed an added dimension to the ...

Isolation and characterization of a novel substrate for the pro-apoptotic Omi/HtrA2 protease

The Wilms' Tumor Suppressor Protein WT1 Is Processed by the Serine Protease HtrA2/Omi

The Wilms' tumor suppressor protein WT1 functions as a transcriptional regulator of genes controlling growth, apoptosis, and differentiation. It has become clear that WT1 can act as an oncogene in many tumors, primarily through the inhibition of apoptosis. Here, we identify the serine protease HtrA2 as a WT1 binding partner and find that it cleaves WT1 at multiple sites following the treatment ...