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* Residue conservation analysis
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DOI no:
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EMBO J
25:3144-3155
(2006)
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PubMed id:
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X-ray crystal structure of MENT: evidence for functional loop-sheet polymers in chromatin condensation.
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S.McGowan,
A.M.Buckle,
J.A.Irving,
P.C.Ong,
T.A.Bashtannyk-Puhalovich,
W.T.Kan,
K.N.Henderson,
Y.A.Bulynko,
E.Y.Popova,
A.I.Smith,
S.P.Bottomley,
J.Rossjohn,
S.A.Grigoryev,
R.N.Pike,
J.C.Whisstock.
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ABSTRACT
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Most serpins are associated with protease inhibition, and their ability to form
loop-sheet polymers is linked to conformational disease and the human
serpinopathies. Here we describe the structural and functional dissection of how
a unique serpin, the non-histone architectural protein, MENT (Myeloid and
Erythroid Nuclear Termination stage-specific protein), participates in DNA and
chromatin condensation. Our data suggest that MENT contains at least two
distinct DNA-binding sites, consistent with its simultaneous binding to the two
closely juxtaposed linker DNA segments on a nucleosome. Remarkably, our studies
suggest that the reactive centre loop, a region of the MENT molecule essential
for chromatin bridging in vivo and in vitro, is able to mediate formation of a
loop-sheet oligomer. These data provide mechanistic insight into chromatin
compaction by a non-histone architectural protein and suggest how the structural
plasticity of serpins has adapted to mediate physiological, rather than
pathogenic, loop-sheet linkages.
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Selected figure(s)
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Figure 5.
Figure 5 (A) The structure of cleaved MENT[WT] labelled as in
Figure 1A. The termini of the M-loop (between hC and hD) are
indicated by ^*. (B) Superposition of native (green) and cleaved
(brown) MENT[WT]. The change in conformation at the top of the
D-helix is indicated by a dotted square and shown in the inset.
Hydrogen bonds are shown by dashed lines and R109, N110, Y112,
F105 and A104 are labelled. (C) CCP4MG (Potterton et al, 2002,
2004) electrostatic potential surface of cleaved MENT[WT],
coloured as in Figure 1B.
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Figure 6.
Figure 6 (A) Structure of the native MENT[  Mloop]
tetramer in the asymmetric unit. Each monomer is coloured
differently; the orange and green monomers form a 'back to back'
dimer (indicated by a dotted oval); the orange molecule forms a
loop–sheet linkage (arrow) to the cyan molecule and a
loop–sheet linkage to the magenta molecule. hD and hE are
labelled. (B) Loop–sheet hydrogen bonds formed by the RCL
(brown) of one molecule with the s6A of an adjoining molecule
(green). Hydrogen bonds are shown as magenta broken lines. (C)
Comparison of native MENT[WT] (blue) and MENT[ Mloop]
(green) reveals conformational change in the C-terminus
(labelled) and s5A/s6A of the A  -sheet
of MENT[ Mloop]
in response to the interaction with the RCL of a neighbouring
molecule (magenta). Note also the different trajectory of the
RCL (labelled).
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
EMBO J
(2006,
25,
3144-3155)
copyright 2006.
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Figures were
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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M.A.Adams-Cioaba,
J.C.Krupa,
C.Xu,
J.S.Mort,
and
J.Min
(2011).
Structural basis for the recognition and cleavage of histone H3 by cathepsin L.
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Nat Commun,
2,
197.
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PDB codes:
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J.A.Huntington,
and
J.C.Whisstock
(2010).
Molecular contortionism - on the physical limits of serpin 'loop-sheet' polymers.
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Biol Chem,
391,
973-982.
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S.Ricagno,
M.Pezzullo,
A.Barbiroli,
M.Manno,
M.Levantino,
M.G.Santangelo,
F.Bonomi,
and
M.Bolognesi
(2010).
Two latent and two hyperstable polymeric forms of human neuroserpin.
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Biophys J,
99,
3402-3411.
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B.Gooptu,
and
D.A.Lomas
(2009).
Conformational pathology of the serpins: themes, variations, and therapeutic strategies.
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Annu Rev Biochem,
78,
147-176.
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B.Gooptu,
E.Miranda,
I.Nobeli,
M.Mallya,
A.Purkiss,
S.C.Brown,
C.Summers,
R.L.Phillips,
D.A.Lomas,
and
T.E.Barrett
(2009).
Crystallographic and cellular characterisation of two mechanisms stabilising the native fold of alpha1-antitrypsin: implications for disease and drug design.
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J Mol Biol,
387,
857-868.
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PDB codes:
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P.C.Ong,
S.J.Golding,
M.C.Pearce,
J.A.Irving,
S.A.Grigoryev,
D.Pike,
C.G.Langendorf,
T.A.Bashtannyk-Puhalovich,
S.P.Bottomley,
J.C.Whisstock,
R.N.Pike,
and
S.McGowan
(2009).
Conformational change in the chromatin remodelling protein MENT.
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PLoS ONE,
4,
e4727.
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T.A.Murray-Rust,
F.K.Kerr,
A.R.Thomas,
T.Wu,
T.Yongqing,
P.C.Ong,
N.S.Quinsey,
J.C.Whisstock,
I.C.Wagenaar-Bos,
C.Freeman,
and
R.N.Pike
(2009).
Modulation of the proteolytic activity of the complement protease C1s by polyanions: implications for polyanion-mediated acceleration of interaction between C1s and SERPING1.
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Biochem J,
422,
295-303.
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J.Zlatanova,
C.Seebart,
and
M.Tomschik
(2008).
The linker-protein network: control of nucleosomal DNA accessibility.
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Trends Biochem Sci,
33,
247-253.
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R.H.Law,
T.Sofian,
W.T.Kan,
A.J.Horvath,
C.R.Hitchen,
C.G.Langendorf,
A.M.Buckle,
J.C.Whisstock,
and
P.B.Coughlin
(2008).
X-ray crystal structure of the fibrinolysis inhibitor alpha2-antiplasmin.
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Blood,
111,
2049-2052.
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PDB code:
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S.H.Li,
N.V.Gorlatova,
D.A.Lawrence,
and
B.S.Schwartz
(2008).
Structural differences between active forms of plasminogen activator inhibitor type 1 revealed by conformationally sensitive ligands.
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J Biol Chem,
283,
18147-18157.
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S.J.McBryant,
C.Krause,
C.L.Woodcock,
and
J.C.Hansen
(2008).
The silent information regulator 3 protein, SIR3p, binds to chromatin fibers and assembles a hypercondensed chromatin architecture in the presence of salt.
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Mol Cell Biol,
28,
3563-3572.
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T.H.Roberts,
and
J.Hejgaard
(2008).
Serpins in plants and green algae.
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Funct Integr Genomics,
8,
1.
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P.C.Ong,
S.McGowan,
M.C.Pearce,
J.A.Irving,
W.T.Kan,
S.A.Grigoryev,
B.Turk,
G.A.Silverman,
K.Brix,
S.P.Bottomley,
J.C.Whisstock,
and
R.N.Pike
(2007).
DNA accelerates the inhibition of human cathepsin v by serpins.
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J Biol Chem,
282,
36980-36986.
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T.Nikitina,
R.P.Ghosh,
R.A.Horowitz-Scherer,
J.C.Hansen,
S.A.Grigoryev,
and
C.L.Woodcock
(2007).
MeCP2-chromatin interactions include the formation of chromatosome-like structures and are altered in mutations causing Rett syndrome.
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J Biol Chem,
282,
28237-28245.
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J.C.Whisstock,
and
S.P.Bottomley
(2006).
Molecular gymnastics: serpin structure, folding and misfolding.
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Curr Opin Struct Biol,
16,
761-768.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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