PDBsum entry 1ry4

Cell adhesion

PDB id: 1ry4

Contents

Protein chain

128 a.a. *

* Residue conservation analysis

PDB id:

1ry4

Name:

Cell adhesion

Title:

Nmr structure of the crib-pdz module of par-6

Structure:

Cg5884-pa. Chain: a. Fragment: crib-pdz domain. Engineered: yes

Source:

Drosophila melanogaster. Fruit fly. Organism_taxid: 7227. Gene: par-6. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

NMR struc:

20 models

Authors:

F.C.Peterson,R.R.Penkert,B.F.Volkman,K.E.Prehoda

Key ref:

F.C.Peterson et al. (2004). Cdc42 regulates the Par-6 PDZ domain through an allosteric CRIB-PDZ transition. Mol Cell, 13, 665-676. PubMed id: 15023337 DOI: 10.1016/S1097-2765(04)00086-3

Date:

19-Dec-03 Release date: 23-Mar-04

Protein chain

O97111  (O97111_DROME) -  LD29223p from Drosophila melanogaster

Seq: 351 a.a.

Struc: 128 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1016/S1097-2765(04)00086-3

Mol Cell 13:665-676 (2004)

PubMed id: 15023337

Cdc42 regulates the Par-6 PDZ domain through an allosteric CRIB-PDZ transition.

F.C.Peterson, R.R.Penkert, B.F.Volkman, K.E.Prehoda.

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.

Selected figure(s)

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.

Figures were selected by an automated process.