4RI0

Serine Protease HtrA3, mutationally inactivated

Summary for 4RI0

• Entry DOI: 10.2210/pdb4ri0/pdb
• Descriptor: Serine protease HTRA3, PHOSPHATE ION (3 entities in total)
• Functional Keywords: structural genomics, psi-biology, midwest center for structural genomics, mcsg, national science center - poland, protease, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Secreted : P83110
• Total number of polymer chains: 3
• Total formula weight: 109126.82

Authors

Osipiuk, J.,Glaza, P.,Wenta, T.,Lipinska, B.,Joachimiak, A.,Midwest Center for Structural Genomics (MCSG) (deposition date: 2014-10-03, release date: 2014-10-29, Last modification date: 2023-09-20)

Primary citation

Glaza, P.,Osipiuk, J.,Wenta, T.,Zurawa-Janicka, D.,Jarzab, M.,Lesner, A.,Banecki, B.,Skorko-Glonek, J.,Joachimiak, A.,Lipinska, B.
Structural and Functional Analysis of Human HtrA3 Protease and Its Subdomains.
Plos One, 10:e0131142-e0131142, 2015

PubMed Abstract: 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 dispensable for HtrA3 activity. As determined by size exclusion chromatography, ΔN-HtrA3 formed stable trimers while both ΔN-HtrA3-ΔPDZ and ΔN-HtrA3S were monomeric. This suggests that the presence of the PDZ domain, unlike in HtrA1 and HtrA2, influences HtrA3 trimer formation. The unique C-terminal sequence of ΔN-HtrA3S appeared to have little effect on activity and oligomerization. Additionally, we examined the cleavage specificity of ΔN-HtrA3. Results reported in this paper provide new insights into the structure and function of ΔN-HtrA3, which seems to have a unique combination of features among human HtrA proteases.

PubMed: 26110759
DOI: 10.1371/journal.pone.0131142

Experimental method

X-RAY DIFFRACTION (3.272 Å)