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PDBsum entry 3fcu
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Cell adhesion/blood clotting
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PDB id
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3fcu
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References listed in PDB file
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Key reference
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Title
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Structure of a complete integrin ectodomain in a physiologic resting state and activation and deactivation by applied forces.
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Authors
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J.Zhu,
B.H.Luo,
T.Xiao,
C.Zhang,
N.Nishida,
T.A.Springer.
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Ref.
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Mol Cell, 2008,
32,
849-861.
[DOI no: ]
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PubMed id
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Abstract
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The complete ectodomain of integrin alpha(IIb)beta(3) reveals a bent, closed,
low-affinity conformation, the beta knee, and a mechanism for linking
cytoskeleton attachment to high affinity for ligand. Ca and Mg ions in the
recognition site, including the synergistic metal ion binding site (SyMBS), are
loaded prior to ligand binding. Electrophilicity of the ligand-binding Mg ion is
increased in the open conformation. The beta(3) knee passes between the
beta(3)-PSI and alpha(IIb)-knob to bury the lower beta leg in a cleft, from
which it is released for extension. Different integrin molecules in crystals and
EM reveal breathing that appears on pathway to extension. Tensile force applied
to the extended ligand-receptor complex stabilizes the closed, low-affinity
conformation. By contrast, an additional lateral force applied to the beta
subunit to mimic attachment to moving actin filaments stabilizes the open,
high-affinity conformation. This mechanism propagates allostery over long
distances and couples cytoskeleton attachment of integrins to their
high-affinity state.
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Figure 3.
Figure 3. Metal Ion Rearrangements in β I Domain Activation
(A) Superposition of headpieces from our unliganded-closed
structure and liganded-open α[IIb]β[3] (Springer et al.,
2008). The β I and hybrid domains are yellow (open) and magenta
(closed), while PSI and I-EGF1 domains are red and green,
respectively. The α headpieces are cyan (open) and gray
(closed).
(B) Enlarged view of β I domains with major
differences in yellow (open) and magenta (closed).
(C and
D) β I domain metal coordination sites in unliganded-closed
α[IIb]β[3] (C) and liganded-open α[IIb]β[3] (D). Ca (gold)
and Mg (green) ions are large spheres; waters (red or pink) are
smaller spheres. N atoms are blue and O atoms are red or pink.
Metal coordination and hydrogen bonds are dashed. The loop
bearing M335 moves far away in (D).
(E) Superposition at
the β I MIDAS.
(F) Superposition at the α I MIDAS of
unliganded-closed (PDB code 1LFA) and liganded-open α[L] (PDB
code 1T0P) in the same orientation as the β I MIDAS in (D). In
(C)–(F), carbons for unliganded-closed and liganded-open
integrins and for ligands are wheat, gray, and cyan,
respectively.
(G and H) Electrostatic potential surfaces at
the unliganded (G) and liganded (H) binding sites.
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Figure 5.
Figure 5. The Integrin Cycle
(A) In the bent
conformation, integrins have low affinity for ligand.
(B)
At sites where actin filaments are formed, the integrin β
subunit cytoplasmic domain binds through talin or kindlins.
Lateral translocation on the cell surface and buffeting cause
integrin extension. Both open and closed headpiece conformations
are putatively present.
(C) Binding to an immobilized
extracellular ligand greatly increases the lateral force and
markedly favors the high-affinity, open headpiece conformation.
(D) Disassembly of the actin cytoskeleton removes the
lateral force. Tensile force between the ligand and the integrin
cytoplasmic domains favors the closed headpiece conformation and
ligand dissociation.
(E) Ligand dissociates, further
favoring the closed headpiece conformation.
(F) In the
absence of ligand and tensile force, the bent conformation is
favored, completing the cycle, and the integrin returns to the
same state as shown in (A).
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The above figures are
reprinted
from an Open Access publication published by Cell Press:
Mol Cell
(2008,
32,
849-861)
copyright 2008.
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