HTRA2
Митохондриальная сериновая протеаза HTRA2 кодируется геном HTRA2. Эта протеаза проявляет протеолитическую активность в отношении неспецифического субстрата бета-казеина. Способствует или индуцирует гибель клеток либо путем прямого связывания и ингибирования белков BIRC (ингибиторами белков апоптоза), что приводит к увеличению активности каспазы, либо с помощью biRC-независимого ингибирования, каспазо-независимого и серинпротеазно-зависимого механизма. Расщепляет THAP5 и способствует его деградации во время апоптоза.
The HTRA2 protein, also called Omi, is a serine protease encoded by the HTRA2 gene. It belongs to the HtrA family of evolutionarily conserved ATP-independent serine proteases, homologs of the HtrA (DegP) serine protease from the bacterium Escherichia coli. HTRA2/Omi is expressed as a 49-kDa proenzyme targeted to the mitochondrial intermembrane space (IMS), where it undergoes proteolytic maturation via cleavage of the first 133 N-terminal residues. The full-length HtrA2 contains the N-terminal mitochondrial targeting sequence, a transmembrane domain, followed by a serine protease domain with the catalytic triad His198-Asp228-Ser306, and a C-terminal PDZ domain. The mature HTRA2/Omi was identified as a mitochondrial direct BIR3-binding protein and a caspase activator. Like mature Smac (also known as DIABLO), mature HTRA2/Omi contains a conserved IAP-binding motif (AVPS) at its N terminus, which is exposed after processing of its N-terminal mitochondrial targeting sequence upon import into the mitochondria. During apoptosis, mature HTRA2/Omi is released together with mature Smac/DIABLO from the mitochondria into the cytosol upon disruption of the outer mitochondrial membrane during apoptosis. Finally, mature HTRA2/Omi induces apoptosis in human cells in a caspase-independent manner through its protease activity and in a caspase-dependent manner via its ability to disrupt caspase-IAP (inhibitor of apoptosis protein) interaction through its Reaper-like motif. Ser306 is the active site of the protease domain, and mutation of Ser306 inactivates HTRA2/Omi. Ser142 and Ser400 are the known phosphorylation sites of HtrA2/Omi. Upon oxidative stress, p38 MAPK phosphorylates Ser142 of HTRA2/Omi in a PINK1-dependent manner. CDK5 phosphorylates Ser400 of HTRA2/Omi in a p38-dependent manner, resulting in the enhancement of HTRA2/Omi proteolytic activity and increased resistance of cells to mitochondrial stress. HTRA2/Omi has, therefore, been proposed to be a pro-apoptotic protein. Additionally, HTRA2/Omi is required for maintaining mitochondrial function. Under normal physiological conditions, HTRA2/Omi acts as a quality control factor and promotes cell survival. Disturbances of the HTRA2/Omi proteolytic activity lead to the accumulation of unfolded proteins in mitochondria, dysfunction of the mitochondrial respiration, generation of reactive oxygen species, and result in a loss of mitochondrial competence. A recent study demonstrated the phosphorylation of HTRA2/Omi at a residue adjacent to a position found mutated in patients with Parkinson's disease. Analysis of available microarray data indicated that the expression of HTRA2 in different cancers varies according to tumor type. |
