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PDBsum entry 4ri0
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References listed in PDB file
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Key reference
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Title
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Structural and functional analysis of human htra3 protease and its subdomains.
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Authors
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P.Glaza,
J.Osipiuk,
T.Wenta,
D.Zurawa-Janicka,
M.Jarzab,
A.Lesner,
B.Banecki,
J.Skorko-Glonek,
A.Joachimiak,
B.Lipinska.
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Ref.
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Plos One, 2015,
10,
e0131142.
[DOI no: ]
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PubMed id
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Abstract
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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.
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