According to the current MEROPS database, HtrA proteases belong to the C subfamily of the S1 family peptidases (chymotrypsin) within the PA clan, with the catalytic triad composed of histidine, aspartate and serine residues. The PDZ domain in prokaryotic HtrAs facilitates substrate binding and regulates oligomer assembly, cellular localization, and protease activities. PDZ is a structural motif found in many signalling proteins and is known to participate in protein–protein interactions.

A unique feature of HtrAs is the presence of a trypsin-like protease domain in combination with one or more C-terminal domains called PDZ. The high temperature requirement A (HtrA) proteins are a family of evolutionarily conserved serine proteases that are found in a large number of organisms ranging from prokaryotes, yeasts, and fungi to plants, birds, fish, and mammals. Collectively, we accentuate that a better understanding of tissue-specific regulation and distinctive physiological and pathological roles of each HtrA will improve our knowledge of many processes that are critical for human health. It is noteworthy that HtrA4 expression has not yet been reported in any primary tumour samples, suggesting an unlikely involvement of this HtrA in cancer. It then reviews the distinctive involvement of each HtrA in various human diseases, especially cancer and pregnancy complications. HtrAs in other species are also briefly mentioned in the context of understanding the human HtrAs. This review first discusses HtrAs broadly and then focuses on the current knowledge of key molecular characteristics of individual human HtrAs, their similarities and differences and their reported physiological functions. The dysregulation of HtrAs has been implicated in many human diseases such as cancer, arthritis, neurogenerative ailments and reproductive disorders. All four HtrAs are active proteases, and their specific cellular and physiological roles depend on tissue type. This limited expression sets HtrA4 apart from the rest of the family. In humans, while HtrA1, 2 and 3 are widely expressed in multiple tissues with variable levels, HtrA4 expression is largely restricted to the placenta with the protein released into maternal circulation during pregnancy. The mammalian high temperature requirement A (HtrA) proteins are a family of evolutionarily conserved serine proteases, consisting of four homologs (HtrA1-4) that are involved in many cellular processes such as growth, unfolded protein stress response and programmed cell death.

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