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PDBsum entry 2ero
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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 structures of vap1 reveal adams' Mdc domain architecture and its unique c-Shaped scaffold.
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Authors
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S.Takeda,
T.Igarashi,
H.Mori,
S.Araki.
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Ref.
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EMBO J, 2006,
25,
2388-2396.
[DOI no: ]
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PubMed id
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Abstract
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ADAMs (a disintegrin and metalloproteinase) are sheddases possessing
extracellular metalloproteinase/disintegrin/cysteine-rich (MDC) domains. ADAMs
uniquely display both proteolytic and adhesive activities on the cell surface,
however, most of their physiological targets and adhesion mechanisms remain
unclear. Here for the first time, we reveal the ADAMs' MDC architecture and a
potential target-binding site by solving crystal structures of VAP1, a snake
venom homolog of mammalian ADAMs. The D-domain protrudes from the M-domain
opposing the catalytic site and constituting a C-shaped arm with cores of Ca2+
ions. The disintegrin-loop, supposed to interact with integrins, is packed by
the C-domain and inaccessible for protein binding. Instead, the hyper-variable
region (HVR) in the C-domain, which has a novel fold stabilized by the strictly
conserved disulfide bridges, constitutes a potential protein-protein adhesive
interface. The HVR is located at the distal end of the arm and faces toward the
catalytic site. The C-shaped structure implies interplay between the ADAMs'
proteolytic and adhesive domains and suggests a molecular mechanism for ADAMs'
target recognition for shedding.
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Figure 1.
Figure 1 MDC architecture. (A) VAP1 dimer viewed from the NCS
axis. The H0-helix, M-domain, linker, D[s]-, D[a]-, C[w]-, and
C[h]-domains and HVRs belonging to the one monomer are shown in
red, yellow, gray, cyan, pink, gray, green and blue,
respectively. The disulfide-linked counterpart is shown in gray.
Zinc and calcium ions are represented as red and black spheres,
respectively. The NAG (N-acetyl-glucosamine, in orange) moieties
linked to Asn218, the calcium-mimetic Lys202 and the bound
inhibitor GM6001 (GM, in green) are in ball-stick
representations. (B) Stereo view of VAP1 monomer from the
direction nearly perpendicular to (A). The helix numbers are
labelled. (C) Superposition of the M-domains of ADAM33 (blue)
and VAP1 (yellow). The calcium ion bound to site I and the zinc
ion in ADAM33 are represented by black and red spheres,
respectively. The disulfide bridges are indicated in black and
blue letters for VAP1 and ADAM33, respectively. The QDHSK
sequence for the dimer interface in VAP1 (residues 320–324) is
in red. (D) Comparison of the calcium-binding site I structures
of ADAM33 (blue) and VAP1 (yellow) in stereo. The residues in
ADAM33 and in VAP1 are labelled in blue and black, respectively.
A calcium ion and a water molecule bound to ADAM33 are
represented as green and red spheres, respectively. The ammonium
group of Lys202 in VAP1 occupies the position of the calcium ion
in ADAM33. In ADAM33 (Orth et al, 2004), side-chain oxygen atoms
of Glu213, Asp296 and Asn407, the carbonyl oxygen of Cys404 and
a water molecule form the corners of a pentagonal bipyramid and
ligand to the calcium ion.
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Figure 4.
Figure 4 C-domain architecture and HVR. (A) The C-domain
architecture in stereo. The C[w]- and C[h]-domains are in gray
and light green, respectively. The disulfide bridges and the
residues forming the hydrophobic ridges are indicated. The HVR
and its NCS counterpart are shown in red and blue, respectively.
The variable loop (residues 539–549), flanked by two adjacent
cysteine residues, is in green. (B) Crystal packing in the
orthorhombic crystal. The crystallographically equivalent
molecules (HVRs) are in cyan (blue) and pink (red),
respectively. The arrows indicate the directions of the HVR
chains. Zinc and calcium ions are represented as red and black
spheres, respectively. (C) Interactions between the HVRs (cyan
and pink) in stereo. The molecular surface of the cyan molecule
is shown with the electrochemical surface potential (red to
blue). The residues constituting the hydrophobic ridges are in
yellow. The residues are labelled in blue and red for cyan and
pink, respectively. (D) Water-mediated hydrogen-bond network in
the HVR. The HVR residues are in pink and cyan; non-HVR residues
in the pink molecule are in gray.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
EMBO J
(2006,
25,
2388-2396)
copyright 2006.
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Secondary reference #1
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Title
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Crystallization and preliminary X-Ray crystallographic analysis of two vascular apoptosis-Inducing proteins (vaps) from crotalus atrox venom.
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Authors
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T.Igarashi,
Y.Oishi,
S.Araki,
H.Mori,
S.Takeda.
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Ref.
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Acta Crystallograph Sect F Struct Biol Cryst Commun, 2006,
62,
688-691.
[DOI no: ]
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PubMed id
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Note In the PDB file this reference is
annotated as "TO BE PUBLISHED".
The citation details given above were identified by an automated
search of PubMed on title and author
names, giving a
perfect match.
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Figure 2.
Figure 2 VAP2 crystals. (a) Form 2-2, (b) form 2-3, (c) form
2-4 and (d) form 2-5 crystals. The scale bars indicate 0.1 mm.
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The above figure is
reproduced from the cited reference
which is an Open Access publication published by the IUCr
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