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PDBsum entry 1p3r
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Signaling protein
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PDB id
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1p3r
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Crystal structures of the dab homology domains of mouse disabled 1 and 2.
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Authors
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M.Yun,
L.Keshvara,
C.G.Park,
Y.M.Zhang,
J.B.Dickerson,
J.Zheng,
C.O.Rock,
T.Curran,
H.W.Park.
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Ref.
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J Biol Chem, 2003,
278,
36572-36581.
[DOI no: ]
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PubMed id
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Abstract
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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.
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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.
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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.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2003,
278,
36572-36581)
copyright 2003.
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