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PDBsum entry 1lcy
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Contents |
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* Residue conservation analysis
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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 insights into the pro-Apoptotic function of mitochondrial serine protease htra2/omi.
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Authors
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W.Li,
S.M.Srinivasula,
J.Chai,
P.Li,
J.W.Wu,
Z.Zhang,
E.S.Alnemri,
Y.Shi.
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Ref.
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Nat Struct Biol, 2002,
9,
436-441.
[DOI no: ]
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PubMed id
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Abstract
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HtrA2/Omi, a mitochondrial serine protease in mammals, is important in
programmed cell death. However, the underlining mechanism of HtrA2/Omi-mediated
apoptosis remains unclear. Analogous to the bacterial homolog HtrA (DegP), the
mature HtrA2 protein contains a central serine protease domain and a C-terminal
PDZ domain. The 2.0 A crystal structure of HtrA2/Omi reveals the formation of a
pyramid-shaped homotrimer mediated exclusively by the serine protease domains.
The peptide-binding pocket of the PDZ domain is buried in the intimate interface
between the PDZ and the protease domains. Mutational analysis reveals that the
monomeric HtrA2/Omi mutants are unable to induce cell death and are deficient in
protease activity. The PDZ domain modulates HtrA2/Omi-mediated cell death
activity by regulating its serine protease activity. These structural and
biochemical observations provide an important framework for deciphering the
mechanisms of HtrA2/Omi-mediated apoptosis.
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Figure 1.
Figure 1. Structure of HtrA2/Omi. a, Schematic representation
of the HtrA2/Omi monomer. The serine protease and the PDZ
domains are colored cyan and pink, respectively. The flexible
linker between the two domains is represented by a dotted line.
The position of the catalytic Ser 306 is highlighted in red. b,
A close-up view of the intramolecular hydrophobic contacts
between the protease and the PDZ domains. Residues from the
protease and the PDZ domains are shown in yellow and orange,
respectively. c, Superposition of the PDZ domains from HtrA2/Omi
(pink) and the membrane-associated protein syntrophin (green,
PDB entry 2PDZ)31. Strands  5/
6
from the serine protease domain and the syntrophin-bound peptide
are shown in cyan and dark blue, respectively. d, Sequence
alignment of the human HtrA proteins and their homolog in E.
coli. The alignment was generated by ClustalW32. The secondary
structural elements are indicated above the alignment. The
catalytic triad residues are boxed in red, and regions critical
for homotrimerization or intramolecular contacts are indicated
below the alignment. Conserved residues are boxed in yellow.
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Figure 2.
Figure 2. HtrA2/Omi forms a pyramid-shaped homotrimer. a, The
HtrA2/Omi trimer is viewed either along (left) or perpendicular
to (right) the three-fold symmetry axis. Trimerization is
mediated exclusively by the serine protease domain. The
N-terminal IAP-binding tetrapeptide motif is located at the top
of the pyramid, and the PDZ domain is at the base. b, Surface
representation of the HtrA2/Omi structure. White arrows indicate
the positions of the catalytic Ser residues. c, A slice of
HtrA2/Omi structure to highlight the position of the catalytic
residue. The HtrA2/Omi surface is represented by color-coded
mesh, with the same scheme as in (a,b) and an orientation
similar to that in (a, right). d, A stereo view of part of the
trimerization interface. The three HtrA2/Omi monomers are
colored green, orange and blue, with their side chains in red.
Three aromatic residues from each monomer interdigitate to form
a tighly packed hydrophobic interface. The experimental electron
density, contoured at 1.5  ,
is shown in green around the three aromatic residues.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Biol
(2002,
9,
436-441)
copyright 2002.
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