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PDBsum entry 3kmu
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Cell adhesion
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PDB id
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3kmu
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References listed in PDB file
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Key reference
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Title
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The pseudoactive site of ilk is essential for its binding to alpha-Parvin and localization to focal adhesions.
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Authors
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K.Fukuda,
S.Gupta,
K.Chen,
C.Wu,
J.Qin.
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Ref.
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Mol Cell, 2009,
36,
819-830.
[DOI no: ]
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PubMed id
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Abstract
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Integrin-linked kinase (ILK) plays a pivotal role in connecting transmembrane
receptor integrin to the actin cytoskeleton and thereby regulating diverse
cell-adhesion-dependent processes. The kinase domain (KD) of ILK is
indispensable for its function, but the underlying molecular basis remains
enigmatic. Here we present the crystal structure of the ILK KD bound to its
cytoskeletal regulator, the C-terminal calponin homology domain of alpha-parvin.
While maintaining a canonical kinase fold, the ILK KD displays a striking
pseudoactive site conformation. We show that rather than performing the kinase
function, this conformation specifically recognizes alpha-parvin for promoting
effective assembly of ILK into focal adhesions. The alpha-parvin-bound ILK KD
can simultaneously engage integrin beta cytoplasmic tails. These results thus
define ILK as a distinct pseudokinase that mechanically couples integrin and
alpha-parvin for mediating cell adhesion. They also highlight functional
diversity of the kinase fold and its "active" site in mediating many biological
processes.
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Figure 2.
Figure 2. Structural Comparison of the Activation Segment
(A) An orthogonal view of the activation segment. (Left)
The activation segment (green) in ILK KD. The side chains of
S343 and E238 (αC helix) are depicted in stick models. (Right)
The activation segment (yellow) in PKA.
(B) Divergent
activation segment in the ILK KD structure. (Left) Overall tube
model of the ILK KD and the location of the activation segment
that can interact with a cluster of hydrophobic residues in the
N-lobe. (Right) A detailed view of hydrophobic and polar
interactions formed between the activation segment and the
N-lobe (<4 Å). See also Figure S2.
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Figure 7.
Figure 7. Hydrophobic Spine Motifs in Active Kinases and ILK
(A) Overall structure of the ILK KD and location of the
hydrophobic spine motifs. The hydrophobic residues in the
regulatory (R) and catalytic (C) spines are depicted in stick
models rendered in the transparent surfaces colored in green and
blue, respectively. The conserved αF helix and the aspartate
residue D374 are highlighted.
(B) Close-up view of the R-
and C-spine motifs in the ILK KD apo form.
(C) Close-up
view of the R- and C-spine motifs in the ILK KD bound to Mg and
ATP. ATP has no effect on the spines.
(D) Close-up view of
the R- and C-spine motifs in inactive protein kinase CDK2 (PDB
ID 1HCL) (apo form).
(E) Close-up view of the R- and
C-spine motifs in the active CDK2 (PDB ID 1FIN) bound to ATP.
Note that the R-spine motif is disrupted in (D), as compared to
those in ILK KD in (C) and active CDK2 in (E).
(F) Overlay
of the R- and C-spine motifs, and other key segments between the
ATP-bound ILK KD and the active CDK2, showing a similar spine
formation between ILK and active CDK2 kinase. See also Figure S7.
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The above figures are
reprinted
by permission from Cell Press:
Mol Cell
(2009,
36,
819-830)
copyright 2009.
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