HtrA Protease Family as Therapeutic Targets

Structural insights into the activation mechanisms of human HtrA serine proteases

“…Additionally, the HtrA PDZ domain may also bind short internal sequences of target proteins, however, it is likely that such interactions are not common and accommodation of the extreme C-termini of target proteins/peptide ligands is preferred [96]. The peptide specificity of the HtrA PDZ domains is consistent with the general function of HtrA proteases which act as protein quality control factors and recognize the extended hydrophobic stretches exposed by misfolded proteins [3].…”

“…The connection between the latter and HtrA2 has been supported by the finding that HtrA2 participates in metabolism of the amyloid precursor proteins (reviewed by Ref. [3]). The association of HtrA2 with Parkinson's disease arises from observations of the motor neuron degeneration (mnd2) mice which carry a missense mutation Ser276Cys significantly reducing proteolytic activity of HtrA2 [67], and of the HtrA2-knockout mice [68].…”

“…in the Escherichia coli HtrA or DegQ) this trimeric pyramidal unit may further oligomerize, forming hexamers, dodecamers (12-mers) or icosatetramers (24-mers), which form hollow cage-like structures with interior active sites (reviewed by Refs. [3,8]). …”

Design and synthesis of new substrates of HtrA2 protease

“…HtrA2 degrades the aberrant, unfolded proteins displaying hydrophobic regions and may function as a chaperone protecting protein structure. It also recognizes specific protein substrates, including regulatory proteins, and thus participates in regulation of many pathways [1][2][3][4]. The physiological substrates of HtrA2 include apoptotic (e.g.…”

“…Amyloid Precursor Protein, Parkin) and many other proteins (e.g. EndoG, P73α, PDHB, WARTS) [3]. Under stressful conditions, HtrA2 may switch from a protecting protein into a proapoptotic factor.…”