HTRA2 is synthesized as a precursor protein and is processed to its mature form within the mitochondria. The mature protein contains a serine protease domain and a PDZ domain, which are crucial for its proteolytic activity and substrate recognition, respectively . The protein is involved in the degradation of misfolded or damaged proteins within the mitochondria, thereby maintaining mitochondrial function and integrity .
One of the key functions of HTRA2 is its role in apoptosis. Under stress conditions, HTRA2 is released from the mitochondria into the cytosol, where it interacts with and cleaves various substrates, including inhibitor of apoptosis proteins (IAPs). This cleavage leads to the activation of caspases, which are the executioners of apoptosis . Thus, HTRA2 acts as a pro-apoptotic factor, promoting cell death in response to cellular stress.
Mutations in the HTRA2 gene have been associated with several diseases, including Parkinson’s disease and 3-methylglutaconic aciduria, type VIII . In Parkinson’s disease, mutations in HTRA2 are thought to impair its proteolytic activity, leading to the accumulation of damaged proteins and mitochondrial dysfunction, which contribute to the degeneration of dopaminergic neurons .
Recombinant HTRA2 is produced using various expression systems, such as E. coli, to study its structure, function, and role in disease. The recombinant protein is often used in biochemical assays to investigate its proteolytic activity and interactions with other proteins . For instance, recombinant HTRA2 has been shown to cleave beta-casein, a model substrate, demonstrating its protease activity .
HTRA2 is a subject of extensive research due to its dual role in maintaining mitochondrial homeostasis and regulating apoptosis. Studies have shown that HTRA2 is involved in the response to cellular stress and the regulation of mitochondrial dynamics . Additionally, HTRA2 is being investigated as a potential therapeutic target for diseases associated with mitochondrial dysfunction and impaired apoptosis, such as neurodegenerative diseases and cancer .