PDBsum entry 1mfl

Signaling protein

PDB id: 1mfl

Contents

Protein chain

95 a.a. *

Ligands

LEU-ASP-VAL-PRO-VAL

Waters ×72

* Residue conservation analysis

PDB id:

1mfl

Name:

Signaling protein

Title:

The structure of erbin pdz domain bound to the carboxy-terminal tail of the erbb2 receptor

Structure:

Erb-b2 interacting protein. Chain: a. Fragment: pdz domain. Engineered: yes. Phosphorylated erb-b2 carboxyl-terminal fragment.. Chain: b. Fragment: peptide ldvpv. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes. Other_details: peptide synthesized chemically

Biol. unit:

Dimer (from PQS)

Resolution:

1.88Å R-factor: 0.169 R-free: 0.216

Authors:

G.Birrane,J.Chung,J.A.Ladias

Key ref:

G.Birrane et al. (2003). Novel mode of ligand recognition by the Erbin PDZ domain. J Biol Chem, 278, 1399-1402. PubMed id: 12444095 DOI: 10.1074/jbc.C200571200

Date:

12-Aug-02 Release date: 21-Jan-03

Protein chain

Q96RT1  (ERBIN_HUMAN) -  Erbin from Homo sapiens

Seq: 1412 a.a.

Struc: 95 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

DOI no: 10.1074/jbc.C200571200

J Biol Chem 278:1399-1402 (2003)

PubMed id: 12444095

Novel mode of ligand recognition by the Erbin PDZ domain.

G.Birrane, J.Chung, J.A.Ladias.

ABSTRACT

Erbin contains a class I PDZ domain that binds to the C-terminal region of the receptor tyrosine kinase ErbB2, a class II ligand. The crystal structure of the human Erbin PDZ bound to the peptide EYLGLDVPV corresponding to the C-terminal residues 1247-1255 of human ErbB2 has been determined at 1.25-A resolution. The Erbin PDZ deviates from the canonical PDZ fold in that it contains a single alpha-helix. The isopropyl group of valine at position -2 of the ErbB2 peptide interacts with the Erbin Val(1351) and displaces the peptide backbone away from the alpha-helix, elucidating the molecular basis of class II ligand recognition by a class I PDZ domain. Strikingly, the phenolic ring of tyrosine -7 enters into a pocket formed by the extended beta 2-beta 3 loop of the Erbin PDZ. Phosphorylation of tyrosine -7 abolishes this interaction but does not affect the binding of the four C-terminal peptidic residues to PDZ, as revealed by the crystal structure of the Erbin PDZ complexed with a phosphotyrosine-containing ErbB2 peptide. Since phosphorylation of tyrosine -7 plays a critical role in ErbB2 function, the selective binding and sequestration of this residue in its unphosphorylated state by the Erbin PDZ provides a novel mechanism for regulation of the ErbB2-mediated signaling and oncogenicity.

Selected figure(s)

Figure 1.
Fig. 1. Structure of the Erbin PDZ bound to the unphosphorylated ErbB2 peptide. A, sequence comparison of selected class I PDZ domains. Identical residues in four or more domains are shown as white letters on blue background. Hyphens represent gaps inserted for optimum alignment. The secondary structure of the Erbin PDZ is indicated at the top. Residues forming a short -helix in PDZs with known structures are enclosed in a red box. B, stereo view of the Erbin PDZ bound to the peptide EYLGLDVPV. The figure was made using BOBSCRIPT (30) and POV-Ray (www.povray.org). C, surface topology of the Erbin PDZ bound to the ErbB2 peptide. The figure was made using GRASP (31). D, two-dimensional representation of the interactions between Erbin PDZ residues (orange) and the peptide (purple). Water molecules (W) are shown as cyan spheres, hydrogen bonds as dashed lines, and hydrophobic interactions as arcs with radial spokes. The figure was made using LIGPLOT (32). E, stereo view of a weighted 2F[obs] F[calc] electron density map at the P[2] pocket calculated at 1.25 Å and contoured at 2.5 .

Figure 2.
Fig. 2. Structure of the Erbin PDZ bound to the phosphorylated ErbB2 peptide. A, stereo view of the Erbin PDZ bound to the peptide EpYLGLDVPV. A weighted 2F[obs] F[calc] electron density map calculated at 1.88-Å resolution and contoured at 1.0 is superimposed on the ErbB2 peptide. B, superposition of the C backbone traces of Erbin PDZ-peptide (pink), Erbin PDZ-phosphopeptide (blue), and PSD-95 PDZ3-peptide (yellow) (Protein Data Bank code 1BE9). Side chains of the peptidic residues, Erbin His1347 and Val1351, and PSD-95 His372 are shown as stick models.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 1399-1402) copyright 2003.