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Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response
Author(s) -
Gray Carol W.,
Ward Robin V.,
Karran Eric,
Turconi Sandra,
Rowles Alison,
Viglienghi Daniela,
Southan Christopher,
Barton Amanda,
Fantom Kenneth G.,
West Andrew,
Savopoulos John,
Hassan Namir J.,
Clinkenbeard Helen,
Hanning Charles,
Amegadzie Bernard,
Davis John B.,
Dingwall Colin,
Livi George P.,
Creasy Caretha L.
Publication year - 2000
Publication title -
european journal of biochemistry
Language(s) - English
Resource type - Journals
eISSN - 1432-1033
pISSN - 0014-2956
DOI - 10.1046/j.1432-1327.2000.01589.x
Subject(s) - tunicamycin , serine protease , proteases , serine , biology , proteolysis , heat shock protein , biochemistry , heat shock , microbiology and biotechnology , protease , unfolded protein response , enzyme , gene
Human HtrA2 is a novel member of the HtrA serine protease family and shows extensive homology to the Escherichia coli HtrA genes that are essential for bacterial survival at high temperatures. HumHtrA2 is also homologous to human HtrA1, also known as L56/HtrA, which is differentially expressed in human osteoarthritic cartilage and after SV40 transformation of human fibroblasts. HumHtrA2 is upregulated in mammalian cells in response to stress induced by both heat shock and tunicamycin treatment. Biochemical characterization of humHtrA2 shows it to be predominantly a nuclear protease which undergoes autoproteolysis. This proteolysis is abolished when the predicted active site serine residue is altered to alanine by site‐directed mutagenesis. In human cell lines, it is present as two polypeptides of 38 and 40 kDa. HumHtrA2 cleaves β‐casein with an inhibitor profile similar to that previously described for E. coli HtrA, in addition to an increase in β‐casein turnover when the assay temperature is raised from 37 to 45 °C. The biochemical and sequence similarities between humHtrA2 and its bacterial homologues, in conjunction with its nuclear location and upregulation in response to tunicamycin and heat shock suggest that it is involved in mammalian stress response pathways.

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