Structural and functional analysis of human HtrA3 protease and its subdomains
Human HtrA3 protease, which induces mitochondria-mediated apoptosis, can be a tumor suppressor and a potential therapeutic target in the treatment of cancer. However, there is little information about its structure and biochemical properties. HtrA3 is composed of an N-terminal domain not required for proteolytic activity, a central serine protease domain and a C-terminal PDZ domain. HtrA3S, its short natural isoform, lacks the PDZ domain which is substituted by a stretch of 7 C-terminal amino acid residues, unique for this isoform. This paper presents the crystal structure of the HtrA3 protease domain together with the PDZ domain (ΔN-HtrA3), showing that the protein forms a trimer whose protease domains are similar to those of human HtrA1 and HtrA2. The ΔN-HtrA3 PDZ domains are placed in a position intermediate between that in the flat saucer-like HtrA1 SAXS structure and the compact pyramidal HtrA2 X-ray structure. The PDZ domain interacts closely with the LB loop of the protease domain in a way not found in other human HtrAs. ΔN-HtrA3 with the PDZ removed (ΔN-HtrA3-ΔPDZ) and an N-terminally truncated HtrA3S (ΔN-HtrA3S) were fully active at a wide range of temperatures and their substrate affinity was not impaired. This indicates that the PDZ domain is dispensablemore »
- Univ. of Gdansk (Poland). Dept. of Biochemistry.
- Argonne National Lab., Argonne, IL (United States). Midwest Center for Structural Genomics and Structural Biology Center.
- Univ. of Gdansk (Poland). Dept. of Molecular and Cellular Biology; Medical Univ. of Gdansk (Poland)
- Centro Nacional de Biotecnologia - CSIC (Spain)
- Publication Date:
- OSTI Identifier:
- Grant/Contract Number:
- Accepted Manuscript
- Journal Name:
- PLoS ONE
- Additional Journal Information:
- Journal Volume: 10; Journal Issue: 6; Journal ID: ISSN 1932-6203
- Public Library of Science
- Research Org:
- Argonne National Lab. (ANL), Argonne, IL (United States)
- Sponsoring Org:
- USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); National Institute of Health; Polish National Science Centre (NCN)
- Country of Publication:
- United States
- 59 BASIC BIOLOGICAL SCIENCES; proteases; crystal structure; protein structure; peptides; oligomers; serine proteases; size-exclusion chromatography; X-ray crystallography
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