Crystal Structures of the Dab Homology Domains of Mouse Disabled 1 and 2

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. 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. The Drosophila disabled gene product (DAB) 1The abbreviations used are: DAB, the Drosophila disabled gene product; DH, DAB homology; Dab1-DH, the DH domain of Dab1; Dab2-DH, the DH domain of Dab2; NPXY, Asp-Pro-X-Try; APP, amyloid precursor protein; Ins-1,4,5-P3, inositol 1,4,5-trisphosphate; PtdIns-4,5-P2, phosphatidylinositol 4,5-diphosphate; PTB/PI, phosphotyrosine binding/phosphotyrosine interaction; apoER2, apolipoprotein E receptor type 2; PH, Pleckstrin homology; HSQC, heteronuclear single quantum coherence spectroscopy; BSA, bovine serum albumin; r.m.s.d., root mean square deviation. was identified as the result of a genetic screen designed to isolate modifier genes of the abl tyrosine kinase (1Bennett R.L. Hoffmann F.M. Development. 1992; 116: 953-966PubMed Google Scholar, 2Gertler F.B. Hill K.K. Clark M.J. Hoffmann F.M. Genes Dev. 1993; 7: 441-453Crossref PubMed Scopus (114) Google Scholar, 3Gertler F.B. Bennett R.L. Clark M.J. Hoffmann F.M. Cell. 1989; 58: 103-113Abstract Full Text PDF PubMed Scopus (209) Google Scholar). Defects in abl and disabled prevent the formation of proper axonal connections in the central nervous system and cause the death of flies during embryonic development. DAB is tyrosine-phosphorylated by the sevenless receptor kinase and functions as an adaptor protein to recruit SH2-SH3 domain proteins to the signaling complex in Drosophila (4Le N. Simon M.A. Mol. Cell. Biol. 1998; 18: 4844-4854Crossref PubMed Scopus (26) Google Scholar). An evolutionarily conserved family of disabled proteins was revealed by the discovery of a 96-kDa growth factor-responsive phosphoprotein possessing an amino-terminal region of ∼150 amino acids that is highly similar to the amino terminus of DAB (5Xu X.X. Yang W. Jackowski S. Rock C.O. J. Biol. Chem. 1995; 270: 14184-14191Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar). DAB family members contain an amino-terminal DAB homology (DH) domain that acts as a protein-protein and protein-phospholipid interaction module and is fused to diverse carboxyl-terminal sequences. The DH domain has been identified in two mammalian proteins, Dab1 (also called mDab) and Dab2 (also known as p96 or Doc-2) (5Xu X.X. Yang W. Jackowski S. Rock C.O. J. Biol. Chem. 1995; 270: 14184-14191Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 6Howell B.W. Gertler F.B. Cooper J.A. EMBO J. 1997; 16: 121-132Crossref PubMed Scopus (303) Google Scholar). 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PubMed Scopus Google Scholar, Cooper J.A. 2001; PubMed Scopus Google and J. Cooper J.A. J.P. PubMed Scopus Google Scholar, M. Rock C.O. M. EMBO J. PubMed Scopus Google in of receptors and cell The DH domain to the Pleckstrin homology of structures N. M. M. 1999; 24: Full Text Full Text PDF PubMed Scopus Google and the phosphotyrosine binding/phosphotyrosine interaction (PTB/PI) domains in proteins in protein-protein interaction and Margolis B. Cell. 1995; Full Text PDF PubMed Scopus Google Scholar, T. Biol. 1999; PubMed Scopus Google Scholar, J.P. Margolis B. 1998; Google Scholar, M. PubMed Scopus Google Scholar). The domains with proteins and binding are to specific functions revealed by structural T. Biol. 1999; PubMed Scopus Google Scholar, J.P. Margolis B. 1998; Google Scholar, M. PubMed Scopus Google Scholar). are three of NPXY binding domains T. Biol. 1999; PubMed Scopus Google Scholar). by and with is The group is by the DH binds to the NPXY sequence M. Borg J.P. Margolis B. Herz J. J. Biol. Chem. 1998; 273,: 33556-33560Abstract Full Text Full Text PDF PubMed Scopus (493) Google Scholar, Cooper J.A. 2001; PubMed Scopus Google Scholar). the the domains of and to NPXY independent of T. Biol. 1999; PubMed Scopus Google Scholar). The domain binds to a that with the peptide binding region Mol. Cell. Biol. 1997; PubMed Google whereas the DH domain binds PtdIns-4,5-P2 independent of the protein interaction B.W. R. Gertler F.B. Cooper J.A. Mol. Cell. Biol. 1999; PubMed Scopus Google Scholar). The structures of domains are and M. 1995; PubMed Scopus Google Scholar, M.J. S. T. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, L. M. S. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, Borg J.P. Margolis B. J. J. EMBO J. 1997; 16: PubMed Scopus Google Scholar). contain a N. M. M. 1999; 24: Full Text Full Text PDF PubMed Scopus Google of a by a carboxyl-terminal The and structures specific binding for whereas the domain of to and peptides. We have the structures of the DH domains of Dab1 and Dab2 to the structural for by the DH domain of the NPXY sequence and We three the Dab2-DH structures in the ligand-free and the binary complex with the NPXY peptide of APP and the Dab1-DH in the ternary complex with the APP peptide and The Dab2-DH structures are the of the structural similarity to We a of the peptide and the binding pockets of Dab1 and was in the ternary complex of Dab1-DH with the peptide and Ins-1,4,5-P3 was Herz J. M.J. Full Text Full Text PDF PubMed Scopus Google Scholar). ternary complex is similar to ternary complex in that two independent binding for the peptide and the two ternary complex structures is the of Ins-1,4,5-P3 in the binding The ternary complex was solved by with PtdIns-4,5-P2, the binding of Ins-1,4,5-P3 in two different ternary complex was solved by with Ins-1,4,5-P3, the the of Ins-1,4,5-P3 in the binding these structural the protein and that are to the of by the Dab1-DH and Dab2-DH a The proteins in and by three and The proteins in a of 1 and 1 We the binary complex of Dab2-DH with the peptide of APP by the The a the in a for We ligand-free Dab2-DH by a different that used for the binary complex We the of the ternary complex of Dab2-DH with the APP peptide and Ins-1,4,5-P3 the of the binary complex or the ligand-free for for the Dab2-DH ternary complex the ternary complex of Dab1-DH with the by different 1 the to a and of and of the binary complex of Dab2-DH and of ligand-free Dab2-DH and the ternary complex of Dab1-DH the of the binary complex and ligand-free Dab2-DH to group with cell of a and a The ternary complex of Dab1-DH to group with cell of a and with the and W. 1997; PubMed Scopus Google Scholar). We used the single with to the protein of the binary complex of Dab2-DH with the APP and in the J. M. Rice T. Biol. 1998; PubMed Scopus Google Scholar). An was in the M. PubMed Scopus Google and in the J. M. Rice T. Biol. 1998; PubMed Scopus Google Scholar). The ligand-free Dab2-DH was by the group and cell similar to of the binary complex of The ternary complex of Dab1-DH was by the of the binary complex of Dab2-DH as a The and functions in the Biol. 1999; PubMed Scopus Google Scholar). in the M. PubMed Scopus Google and in the J. M. Rice T. Biol. 1998; PubMed Scopus Google The and are in and binary complex of of ternary complex of is the of an of the with and and is the mean of that of is the of the root mean square of the to the root mean square of the and is for by the and are and is to that of the for an of the of of of is the of an of the with and and is the mean of that is the of the root mean square of the to the root mean square of the and is for by the and are and is to that of the for an of the of in a NMR 1 Dab1-DH or of two and in a of and Ins-1,4,5-P3 in the was the protein during the of the NMR heteronuclear single quantum coherence spectroscopy with a NMR by the in the as Dab1-DH was with the of the two and with that of the Ins-1,4,5-P3 and by the and S. G. J. J. 1995; PubMed Scopus Google Scholar). The of Scholar). Mutagenesis and of a has been L. S. Curran T. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). was the peptide to the cytoplasmic domain of amyloid protein 1 and a peptide used as a have been R. Rice D.S. Sheldon M. Curran T. J. Neurosci. 1999; PubMed Google Scholar). The to by the with for Dab1 or Dab1 single amino and in cell 1 and of and The with the amyloid protein 1 NPXY peptide or the peptide for 2 The peptide three with the cell and the proteins by to Dab1 was by with the of Dab1 and Dab1 of the was a was used for Mutagenesis and Dab1-DH and Dab2-DH the and and the by the The and of Dab1-DH and and of and by the and proteins in and in The proper of the proteins was confirmed by The PtdIns-4,5-P2 binding of Dab1-DH and Dab2-DH by binding with the proteins and PtdIns-4,5-P2 The with PtdIns-4,5-P2 was with and for 1 to and was with protein in with with The was in and for 1 with a of in with The was 1 in and for 2 with a of to in with the was 1 in and the of protein to PtdIns-4,5-P2 was by the of was to a highly product The was with a system and the protein to the was with the of the DH solved the structures of the DH domain in three different ligand ligand-free the binary complex of Dab2-DH with the NPXY peptide the ternary complex of Dab1-DH with the NPXY peptide and The ligand-free and binary complex structures of Dab2-DH in the group and have three in the two of are by a and of a with a The ternary complex of Dab1-DH has two in the by a in of these three structures are in the ligand-free Dab2-DH and binary complex are and whereas the was for in the ternary complex of of the DH domain of and three The are two that are to a known as the N. M. M. 1999; 24: Full Text Full Text PDF PubMed Scopus Google Scholar, M. PubMed Scopus Google the of the and the of the whereas is of the and the and are the amino and and is and The carboxyl-terminal of the The NPXY peptide binds to the of the the structures of and the of is the of the is by a of and as a binding for Ins-1,4,5-P3 of the in the DH of ligand-free Dab2-DH and binary complex in the APP of and the of and different in the ligand-free Dab2-DH and the binary complex of Dab2-DH the binary complex of Dab2-DH, in with the group of of the APP whereas and are of the binding for of the APP peptide in with the of of the APP peptide and of the in Dab1 binding for the peptide the binary complex of Dab2-DH and the ternary complex of Dab1-DH are to the of and the of the of the and and in the to with the and of Ins-1,4,5-P3, and of these structures suggests that the of the of the DH domain is for two independent for the proteins the NPXY sequence and for the of the APP of the APP peptide binding to the Dab2-DH and the Dab1-DH are in in and in in the APP peptide are that the of tyrosine of the APP peptide the the Dab2-DH and for the in and peptide binding of of the Dab1 DH domain of with Dab1 or Dab1 with the peptide to the amyloid protein 1 cytoplasmic domain (NPXY) or with a peptide with amino The peptide by and Dab1 was by of the by with to of the of Dab1 of inositol of Ins-1,4,5-P3 binding. Ins-1,4,5-P3 are in binds in the of are in for the in Ins-1,4,5-P3 binds to NMR by of Dab1-DH and the of of Ins-1,4,5-P3 the of that are with or in of the DH with the NPXY APP the DH domain is the structures of and the of binding the NPXY of the APP peptide a whereas the an to of the for structures M. 1995; PubMed Scopus Google Scholar, M.J. S. T. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, Borg J.P. Margolis B. J. J. EMBO J. 1997; 16: PubMed Scopus Google and for a Dab1-DH Herz J. M.J. Full Text Full Text PDF PubMed Scopus Google Scholar). The NPXY sequence with is in binding to Dab1 and Dab2 B.W. R. Gertler F.B. Cooper J.A. Mol. Cell. Biol. 1999; PubMed Scopus Google Scholar). The structures have that the group of of the APP peptide is the of in Dab1 in whereas group is to the of in and with the of in and the of in have been in the solved of Dab1-DH Herz J. M.J. Full Text Full Text PDF PubMed Scopus Google Scholar). These binding of with the that tyrosine of the NPXY binding by the DH domain B.W. R. Gertler F.B. Cooper J.A. Mol. Cell. Biol. 1999; PubMed Scopus Google Scholar, Cooper J.A. 2001; PubMed Scopus Google Scholar). The type of the of the NPXY sequence to Dab1 and Dab2 binding. NPXY tyrosine or the to to Dab1 and Dab2 B.W. R. Gertler F.B. Cooper J.A. Mol. Cell. Biol. 1999; PubMed Scopus Google Scholar, Cooper J.A. 2001; PubMed Scopus Google Scholar). The complex structures that the of of the APP peptide binds a with the Dab1-DH and Dab2-DH of two of in the APP peptide structures The of the binding the in the NPXY sequence tyrosine or the of in Dab2-DH is by the of and and in whereas the group of with the of in is to the of in in Dab1-DH, the of is the of in and the of of the APP peptide and with the of in whereas the group of is in interaction with Dab1 the the Dab1-DH Herz J. M.J. Full Text Full Text PDF PubMed Scopus Google of an NPXY peptide to a by similar to in Dab1-DH and Dab2-DH the of protein for binding to the NPXY three Dab1 the Dab1-DH in in in in and in in is in three of domain the the peptide binding by M. 1995; PubMed Scopus Google Scholar). in the group of the interaction with the group of of the APP The Dab1 in a in for the NPXY B.W. R. Gertler F.B. Cooper J.A. Mol. Cell. Biol. 1999; PubMed Scopus Google with the that of Dab1-DH with the of of the NPXY designed the of Dab1 to in plays a role in interaction with tyrosine of the peptide ligand M. 1995; PubMed Scopus Google Scholar). peptide binding of the three Dab1 was binding of the and to the APP NPXY peptide The to the NPXY peptide to the tyrosine-phosphorylated NPXY peptide of the confirmed that the of Dab1 similar of the Dab DH with Dab DH domain binds to PtdIns-4,5-P2, of the inositol in B.W. R. Gertler F.B. Cooper J.A. Mol. Cell. Biol. 1999; PubMed Scopus Google Scholar, M.J. EMBO J. PubMed Scopus Google Scholar). The domain binds and binding is for tyrosine of by receptors Mol. Cell. Biol. 1997; PubMed Google Scholar). the has binding for proteins and the Dab DH domain is to have two independent binding for proteins and B.W. R. Gertler F.B. Cooper J.A. Mol. Cell. Biol. 1999; PubMed Scopus Google Scholar, M.J. EMBO J. PubMed Scopus Google Scholar). Ins-1,4,5-P3 is known to with PtdIns-4,5-P2 for binding to Dab1-DH B.W. R. Gertler F.B. Cooper J.A. Mol. Cell. Biol. 1999; PubMed Scopus Google Scholar). The binding of Ins-1,4,5-P3 to Dab1-DH was confirmed by the of in the NMR the that as Dab1-DH is with Ins-1,4,5-P3, the the that the binding is in the NMR The that of the and that the of the Dab1-DH is binding of of Dab1-DH the binding for Ins-1,4,5-P3, is that of the APP peptide by the The is by the and of of and These for the of the three of Ins-1,4,5-P3 1 and of the and of Ins-1,4,5-P3 and and and the group of Ins-1,4,5-P3 and The group with and and the group with The binding are conserved in Dab2-DH 1 and that Dab2-DH to Ins-1,4,5-P3 in the as The of Dab1-DH that the binding of the head group of PtdIns-4,5-P2 by the as in of Dab1-DH, that the binding of Ins-1,4,5-P3 in two different the is the as that in of Dab1-DH, whereas in the the of the group is the Herz J. M.J. Full Text Full Text PDF PubMed Scopus Google Scholar). These two binding have been an by of the in a to of Dab1-DH with in the Dab DH the domains phosphatidylinositol the N. M. M. 1999; 24: Full Text Full Text PDF PubMed Scopus Google Scholar, M.A. PubMed Scopus Google Scholar). two of three of the are for the binding of are the of the the Mol. Cell. Biol. 1997; PubMed Google Scholar). the of Dab1-DH and and in to the binding of PtdIns-4,5-P2, for or a binding the of Dab1-DH a binding for PtdIns-4,5-P2, whereas the These suggest that the to binding of PtdIns-4,5-P2 in Dab of the APP peptide binding of the Dab1-DH to PtdIns-4,5-P2 that the and of the DH domain are the of the two Dab1-DH and with the of Dab1-DH to Ins-1,4,5-P3, the that by the to the by Ins-1,4,5-P3 binding to that and in Dab1 are in binding to PtdIns-4,5-P2, as in the Dab1-DH We have solved the structures of Dab2-DH in a ligand-free and in complex with the APP These structures the of Dab2-DH and the for the NPXY sequences. We the ternary complex of Dab1-DH with the APP peptide and the ternary complex of Dab1-DH with the peptide and Ins-1,4,5-P3 was Herz J. M.J. 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Full Text PDF PubMed Scopus Google of Dab1 the DH domain is to with the of Dab1 during Reelin the is to in the receptors for Rock C.O. Cooper J.A. EMBO J. PubMed Scopus Google Scholar, M.J. EMBO J. PubMed Scopus Google Scholar, Cooper J.A. 2001; PubMed Scopus Google Scholar). PtdIns-4,5-P2 is to in of the Biol. 2001; PubMed Scopus Google and is to for M. M.A. Biol. 1998; Full Text Full Text PDF PubMed Google Scholar). interaction of Dab2-DH with the NPXY and PtdIns-4,5-P2 receptors with the the carboxyl-terminal region of Dab2 with and the adapter suggests that Dab2 plays a role in the of receptors to for endocytosis. growth receptors are in the M. N. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google of Dab2 in the proteins with growth receptors for structural and have the by the DH domain NPXY an and a the These identified the binding by to Ins-1,4,5-P3 is and that two in the are for binding. We the for protein and We and for and and for with