AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |
Back to Blog
Reaper unfolder12/28/2022 ![]() ![]() These unique features along with its multitasking potential make HtrA2 a promising therapeutic target both in cancer and neurodegeneration.Īlzheimer's disease (AD) is a neurodegenerative disease that is characterized by a devastating decline in cognitive activities among all types of dementia, and it severely affects the quality of life. Therefore, the exclusive structural attributes of HtrA2 that involve multimodal activation, intermolecular PDZ-protease crosstalk, and an allosterically-modulated trimeric active-site ensemble have enabled the protease to evolve across species and partake functions that are fine-tuned for maintaining cellular homeostasis and mitochondrial proteome quality control in humans. Furthermore, its ability to activate a wide repertoire of substrates through both its N- and C-terminal regions presumably has calibrated its association with several cellular pathways and hence diseases including neurodegenerative disorders and cancer. Interestingly, unlike its other human counterparts, HtrA2 has also been implicated in maintaining the mitochondrial integrity through a bi-functional chaperone-protease activity, the on-off switch of which is yet to be identified. This mitochondrial protease upon maturation, exposes its one-of-a-kind N-terminal tetrapeptide (AVPS) motif that binds and subsequently cleaves Inhibitor of Apoptosis Proteins (IAPs) thus promoting cell death, and posing as an important molecule for therapeutic intervention. Despite perpetuating the oligomeric architecture and overall structural fold of its homologs that comprises serine protease and regulatory PDZ domains, subtle conformational alterations and dynamic enzymatic regulation through the distinct allosteric mode of action lead to its functional diversity. Involvement in manifold intricate cellular networks and diverse pathophysiological functions make HtrA2 the most enigmatic moonlighting protease amongst the human HtrAs. Mitochondrial high-temperature requirement protease A2 (HtrA2) is an integral member of the HtrA family of serine proteases that are evolutionarily conserved from prokaryotes to humans. (I) Average number of TH-positive neurons in the substantia nigra pars compacta of wild-type and HtrA2/Omi knockout animals. (G and H) Average optical density of TH staining in both the total basal ganglia and the area where localized degeneration was observed (posterior portion of the basal ganglia). Analysis was performed with both P 20 and P 30 animals. (E and F) Density of NeuN-positive neurons in the striata (Str) of wild-type and HtrA2/Omi knockout mice scored for both the whole striatum (total basal ganglia) and the area where localized degeneration was observed (posterior portion of the basal ganglia). ![]() (D) Diagram of a mouse brain in sagital orientation indicating the area of striatal degeneration (red box) in the striatum. (C) MAP2 immunohistochemistry revealing the loss of this protein in sections from knockout animals (right). ![]() (B) GFAP immunohistochemistry revealing the reaction of astrocytes in knockout animals (right). (A) Hematoxylin and eosin staining showing focal loss of neurons and occasional ballooning in the striata of HtrA2/Omi knockout animals (right) compared to controls ( / ) (left). Morphological features of localized striatal degeneration in HtrA2/Omi knockout mice. Mammalian HtrA2/Omi is therefore likely to function in vivo in a manner similar to that of its bacterial homologues DegS and DegP, which are involved in protection against cell stress, and not like the proapoptotic Reaper family proteins in Drosophila melanogaster. This conclusion is reinforced by the finding that simultaneous deletion of the other major IAP binding protein, Smac/DIABLO, does not obviously alter the phenotype of HtrA2/Omi knockout mice or cells derived from them. The phenotype of these mice suggests that it is the protease function of this protein and not its IAP binding motif that is critical. These animals, or cells derived from them, show no evidence of reduced rates of cell death but on the contrary suffer loss of a population of neurons in the striatum, resulting in a neurodegenerative disorder with a parkinsonian phenotype that leads to death of the mice around 30 days after birth. We report here the phenotype of mice entirely lacking expression of HtrA2/Omi due to targeted deletion of its gene, Prss25. Once in the cytosol, HtrA2/Omi has been implicated in promoting cell death by binding to inhibitor of apoptosis proteins (IAPs) via its amino-terminal Reaper-related motif, thus inducing caspase activity, and also in mediating caspase-independent death through its own protease activity. The serine protease HtrA2/Omi is released from the mitochondrial intermembrane space following apoptotic stimuli. ![]()
0 Comments
Read More
Leave a Reply. |