 |
PDBsum entry 1ry4
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Cell adhesion
|
PDB id
|
|
|
|
1ry4
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Cdc42 regulates the par-6 pdz domain through an allosteric crib-Pdz transition.
|
|
|
Authors
|
|
F.C.Peterson,
R.R.Penkert,
B.F.Volkman,
K.E.Prehoda.
|
|
|
Ref.
|
|
Mol Cell, 2004,
13,
665-676.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Regulation of protein interaction domains is required for cellular signaling
dynamics. Here, we show that the PDZ protein interaction domain from the cell
polarity protein Par-6 is regulated by the Rho GTPase Cdc42. Cdc42 binds to a
CRIB domain adjacent to the PDZ domain, increasing the affinity of the Par-6 PDZ
for its carboxy-terminal ligand by approximately 13-fold. Par-6 PDZ regulation
is required for function as mutational disruption of Cdc42-Par-6 PDZ coupling
leads to inactivation of Par-6 in polarized MDCK epithelial cells. Structural
analysis reveals that the free PDZ domain has several deviations from the
canonical PDZ conformation that account for its low ligand affinity. Regulation
results from a Cdc42-induced conformational transition in the CRIB-PDZ module
that causes the PDZ to assume a canonical, high-affinity PDZ conformation. The
coupled CRIB and PDZ architecture of Par-6 reveals how simple binding domains
can be combined to yield complex regulation.
|
|
|
|
|
|
|
|
Figure 5.
Figure 5. Comparison of Par-6 PDZ Domain in the Free and
Cdc42-Bound Forms(A) Ribbon overlay of the free (green) and
Cdc42 bound (orange) Par-6 PDZ domain. The root mean square
deviation (rmsd) between the free PDZ ensemble is shown compared
to the rmsd between the free ensemble and the Cdc42-bound
structure. The sequence of human Par-6B used for the crystal
structure is shown for comparison.(B) Comparison of the free and
Cdc42-bound Par-6 PDZ domains to other PDZ structures. Known PDZ
structures (black; PDB codes: 1BE9, 1G9O, 1GM1, 1I92, 1IHJ,
1KEF, 1KWA, 1PDR, 1QAU; only residues from the PDZ domains of
these structures are shown) have a tightly clustered
conformation that closely resembles the Cdc42-bound Par-6 PDZ
domain. The free Par-6 structure deviates from the canonical PDZ
fold, however. A statistical analysis of the conformational
differences between the free and Cdc42-bound Par-6 PDZ domains
and PSD-95 PDZ3 (PDB code 1BE9) is shown below the overlay.
|
|
Figure 6.
Figure 6. Par-6 PDZ Peptide Binding Induces Conversion to
the High-Affinity Conformation(A) The free Par-6 PDZ domain
exists in a low-affinity conformation (green) that deviates from
the canonical PDZ conformation. Binding of Cdc42 or peptide
induces conversion to the high-affinity form (orange). Once one
ligand has bound, the other ligand binds with an enhanced
affinity (by a cooperativity factor, c).(B) The Drosophila Par-6
PDZ-VKESLV peptide complex structure. Electron density for the
peptide from a 2F[o] − F[c] map in which the peptide was
omitted from the calculation of the phases is shown.(C)
Comparison of the crystal structure of Par-6 in complex with
VKESLV peptide (orange) and Cdc42-bound Par-6 and PSD-95 PDZ3
(both black).(D) Structure of the peptide binding pocket. The
Par-6 PDZ domain (orange) is shown with bound peptide
(violet).(E) Spatial and temporal Par-6 regulation model. Cdc42
is lipid modified and becomes associated with the membrane when
activated, which may play a role in Par-6 localization thereby
coupling membrane translocation with activity modulation.
|
|
|
|
|
|
The above figures are
reprinted
by permission from Cell Press:
Mol Cell
(2004,
13,
665-676)
copyright 2004.
|
|
|
|
|
|
|
