title: Crystal structures of the Dab homology domains of mouse disabled 1 and 2.
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.
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA.
authors.forename: Mikyung
authors.initials: M
authors.lastname: Yun
authors.forename: Lakhu
authors.initials: L
authors.lastname: Keshvara
authors.forename: Cheon-Gil
authors.initials: CG
authors.lastname: Park
authors.forename: Yong-Mei
authors.initials: YM
authors.lastname: Zhang
authors.forename: J Bradley
authors.initials: JB
authors.lastname: Dickerson
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
authors.forename: Charles O
authors.initials: CO
authors.lastname: Rock
authors.forename: Tom
authors.initials: T
authors.lastname: Curran
authors.forename: Hee-Won
authors.initials: HW
authors.lastname: Park
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000737:chemistry* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism; D018360:Crystallography, X-Ray; D018076:DNA, Complementary / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D015544:Inositol 1,4,5-Trisphosphate / Q000737:chemistry; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry; D010743:Phospholipids / Q000737:chemistry; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D000091042:Reelin Protein; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D016564:Amyloid beta-Protein Precursor; D051017:Apoptosis Regulatory Proteins; C102885:DAB2 protein, human; D018076:DNA, Complementary; C103773:Dab1 protein, mouse; C478773:Dab2 protein, mouse; D008024:Ligands; D009419:Nerve Tissue Proteins; D010455:Peptides; D019269:Phosphatidylinositol 4,5-Diphosphate; D010743:Phospholipids; D011506:Proteins; D000091042:Reelin Protein; D025521:Tumor Suppressor Proteins; D015544:Inositol 1,4,5-Trisphosphate; C000717127:RELN protein, human; C000717128:Reln protein, mouse