PDBsum entry 1p3r

Signaling protein

PDB id: 1p3r

Contents

Protein chains

148 a.a. *

Waters ×315

* Residue conservation analysis

PDB id:

1p3r

Name:

Signaling protein

Title:

Crystal structure of the phosphotyrosin binding domain(ptb) of mouse disabled 1(dab1)

Structure:

Disabled homolog 2. Chain: a, b, c. Fragment: ptb domain of mouse disabled 2. Synonym: doc-2, mitogen-responsive phosphoprotein. Engineered: yes

Source:

Mus musculus. House mouse. Organism_taxid: 10090. Gene: dab2 or doc2. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

2.10Å R-factor: 0.223 R-free: 0.246

Authors:

M.Yun,L.Keshvara,C.G.Park,Y.M.Zhang,J.B.Dickerson,J.Zheng,C.O.Rock, T.Curran,H.W.Park

Key ref:

M.Yun et al. (2003). Crystal structures of the Dab homology domains of mouse disabled 1 and 2. J Biol Chem, 278, 36572-36581. PubMed id: 12826668 DOI: 10.1074/jbc.M304384200

Date:

18-Apr-03 Release date: 05-Aug-03

Protein chains

P98078  (DAB2_MOUSE) -  Disabled homolog 2 from Mus musculus

Seq: 766 a.a.

Struc: 148 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1074/jbc.M304384200

J Biol Chem 278:36572-36581 (2003)

PubMed id: 12826668

Crystal structures of the Dab homology domains of mouse disabled 1 and 2.

M.Yun, L.Keshvara, C.G.Park, Y.M.Zhang, J.B.Dickerson, J.Zheng, C.O.Rock, T.Curran, H.W.Park.

ABSTRACT

Disabled (Dab) 1 and 2 are mammalian homologues of Drosophila DAB. Dab1 is a key cytoplasmic mediator in Reelin signaling that controls cell positioning in the developing central nervous system, whereas Dab2 is an adapter protein that plays a role in endocytosis. DAB family proteins possess an amino-terminal DAB homology (DH) domain that is similar to the phosphotyrosine binding/phosphotyrosine interaction (PTB/PI) domain. We have solved the structures of the DH domains of Dab2 (Dab2-DH) and Dab1 (Dab1-DH) in three different ligand forms, ligand-free Dab2-DH, the binary complex of Dab2-DH with the Asn-Pro-X-Tyr (NPXY) peptide of amyloid precursor protein (APP), and the ternary complex of Dab1-DH with the APP peptide and inositol 1,4,5-trisphosphate (Ins-1,4,5-P3, the head group of phosphatidylinositol-4,5-diphosphate (PtdIns-4,5-P2)). The similarity of these structures suggests that the rigid Dab DH domain maintains two independent pockets for binding of the APP/lipoprotein receptors and phosphoinositides. Mutagenesis confirmed the structural determinants specific for the NPXY sequence and PtdIns-4,5-P2 binding. NMR spectroscopy confirmed that the DH domain binds to Ins-1,4,5-P3 independent of the NPXY peptides. These findings suggest that simultaneous interaction of the rigid DH domain with the NPXY sequence and PtdIns-4,5-P2 plays a role in the attachment of Dab proteins to the APP/lipoprotein receptors and phosphoinositide-rich membranes.

Selected figure(s)

Figure 1.
FIG. 1. Structures of the Dab DH domain. Overview of ligand-free Dab2-DH (A), the binary complex of Dab2-DH with the APP peptide (-7NGYENPTYK+1) (B), and the ternary complex of Dab1-DH with the same APP peptide and Ins-1,4,5-P[3] (C). Helices are shown in cyan, strands are shown in yellow, and other structural elements are shown in brown. The APP peptide is shown in green, whereas carbons of Ins-1,4,5-P[3] binding residues are in yellow (ball and stick representations). Note that the NPXY motif binding site is 25 Å from the binding site for Ins-1,4,5-P[3], consistent with the possible simultaneous binding of the Dab DH domain to peptides and to phosphoinositides (18, 27). D, structural comparison of Dab2-DH with the other NPXY binding PTB/PI domains Shc and X-11 (left to right). The top panels show the NPXY peptides (green), Tyr-0 (carbons, green; ball and stick representation), and the interacting protein residues (carbons, gray; ball and stick representation). The bottom panels show close-up views of the Tyr-0-binding site. Hydrogen bonds are indicated by broken lines.

Figure 3.
FIG. 3. Binding site of the APP peptide. Stereoview of the APP peptide binding to the Dab2-DH (A) and the Dab1-DH (B). Solid lines indicate hydrogen bonds. Carbons are shown in gray in Dab-DH and in green in the APP peptide (selected residues are numbered). Note that the side chain conformation of tyrosine of the APP peptide at the (-5) position differs between the Dab2-DH and Dab1-DH. Boxed residues were mutated for the experiment shown in Fig. 4.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 36572-36581) copyright 2003.

Figures were selected by an automated process.