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PDBsum entry 2znh
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Blood clotting
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PDB id
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2znh
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References listed in PDB file
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Key reference
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Title
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Crystal structure of a stable dimer reveals the molecular basis of serpin polymerization.
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Authors
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M.Yamasaki,
W.Li,
D.J.Johnson,
J.A.Huntington.
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Ref.
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Nature, 2008,
455,
1255-1258.
[DOI no: ]
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PubMed id
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Abstract
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Repeating intermolecular protein association by means of beta-sheet expansion is
the mechanism underlying a multitude of diseases including Alzheimer's,
Huntington's and Parkinson's and the prion encephalopathies. A family of
proteins, known as the serpins, also forms large stable multimers by ordered
beta-sheet linkages leading to intracellular accretion and disease. These
'serpinopathies' include early-onset dementia caused by mutations in
neuroserpin, liver cirrhosis and emphysema caused by mutations in
alpha(1)-antitrypsin (alpha(1)AT), and thrombosis caused by mutations in
antithrombin. Serpin structure and function are quite well understood, and the
family has therefore become a model system for understanding the beta-sheet
expansion disorders collectively known as the conformational diseases. To
develop strategies to prevent and reverse these disorders, it is necessary to
determine the structural basis of the intermolecular linkage and of the
pathogenic monomeric state. Here we report the crystallographic structure of a
stable serpin dimer which reveals a domain swap of more than 50 residues,
including two long antiparallel beta-strands inserting in the centre of the
principal beta-sheet of the neighbouring monomer. This structure explains the
extreme stability of serpin polymers, the molecular basis of their rapid
propagation, and provides critical new insights into the structural changes
which initiate irreversible beta-sheet expansion.
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Figure 1.
Figure 1: Crystallographic structures of active, latent and
self-terminating dimer of the serpin antithrombin. a, Active
antithrombin is shown with the RCL on top (yellow) and the  -sheet
A facing (red, with numbered strands). Either by proteolytic
cleavage in the RCL or by extraction of strand 1C (s1C, orange),
serpins incorporate the RCL into -sheet
A as strand 4A (s4A) resulting in a hyperstable six-stranded
conformation. Polymerogenic mutations are shown (yellow is Z,
magenta is Mmalton, blue is Siiyama and Syracuse, red and cyan
are His338Arg and Gly392Glu neuroserpin^3, and green is P80S
antithrombin^11). The loop connecting strand 6A to 5A is in
cyan. b, The latent conformer of antithrombin is shown coloured
as in a. Residues on strands 5 and 6A, which were mutated to Cys
(see Fig. 2a), are indicated by green balls. c, The structure of
the stable antithrombin dimer (monomer A coloured as in b, and
monomer B is pale green).
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Figure 3.
Figure 3: Models of the serpin polymer and the M* state. a, A
model of a linear serpin dimer (coloured as in Fig. 1c), with
balls indicating AspN cleavage sites found in polymers of
antithrombin (magenta) and  [1]AT
(cyan). The yellow ball shows the position of the Leu303Cys
substitution (Fig. 2c). b, A modelled pentamer was formed by the
addition of protomers to both ends of the dimer. c, A model of
the polymerogenic folding intermediate (M*) with the contiguous
loop from the C terminus of strand 6A to strand 1C in a
random-coil conformation. New proteolytic sites in this region
(magenta balls for antithrombin, cyan balls for [1]AT
and green balls for PAI-1; ref. 20) were detected for the M*
state (Fig. 2d).
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(2008,
455,
1255-1258)
copyright 2008.
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