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PMID: 10373567 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

The disabled 1 phosphotyrosine-binding domain binds to the internalization signals of transmembrane glycoproteins and to phospholipids.

Molecular and cellular biology ·Vol. 19 ·No. 7 ·1999-07-00 ·Pages 5179-88

Howell BW, Lanier LM, Frank R, Gertler FB, Cooper JA

Abstract

Disabled gene products are important for nervous system development in drosophila and mammals. In mice, the Dab1 protein is thought to function downstream of the extracellular protein Reln during neuronal positioning. The structures of Dab proteins suggest that they mediate protein-protein or protein-membrane docking functions. Here we show that the amino-terminal phosphotyrosine-binding (PTB) domain of Dab1 binds to the transmembrane glycoproteins of the amyloid precursor protein (APP) and low-density lipoprotein receptor families and the cytoplasmic signaling protein Ship. Dab1 associates with the APP cytoplasmic domain in transfected cells and is coexpressed with APP in hippocampal neurons. Screening of a set of altered peptide sequences showed that the sequence GYXNPXY present in APP family members is an optimal binding sequence, with approximately 0.5 microM affinity. Unlike other PTB domains, the Dab1 PTB does not bind to tyrosine-phosphorylated peptide ligands. The PTB domain also binds specifically to phospholipid bilayers containing phosphatidylinositol 4P (PtdIns4P) or PtdIns4,5P2 in a manner that does not interfere with protein binding. We propose that the PTB domain permits Dab1 to bind specifically to transmembrane proteins containing an NPXY internalization signal.

MeSH Terms
Amino Acid Sequence Amyloid beta-Protein Precursor/chemistry,metabolism Animals Binding Sites Cloning, Molecular Cytoplasm/metabolism Glycoproteins/metabolism HeLa Cells Humans Ligands Membrane Glycoproteins/metabolism Membrane Lipids/metabolism Mice Molecular Sequence Data Nerve Tissue Proteins/genetics,metabolism Peptides/metabolism Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases Phosphatidylinositols/metabolism Phospholipids/metabolism Phosphoric Monoester Hydrolases/metabolism Phosphorylation Phosphotyrosine/metabolism Receptors, LDL/metabolism Recombinant Fusion Proteins/genetics,metabolism Reelin Protein Saccharomyces cerevisiae Subcellular Fractions Tumor Cells, Cultured
Chemicals
Amyloid beta-Protein Precursor Dab1 protein, mouse Glycoproteins Ligands Membrane Glycoproteins Membrane Lipids Nerve Tissue Proteins Peptides Phosphatidylinositols Phospholipids Receptors, LDL Recombinant Fusion Proteins Reelin Protein Phosphotyrosine Phosphoric Monoester Hydrolases INPPL1 protein, human Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases RELN protein, human Reln protein, mouse
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Howell B W
Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Lanier L M
Frank R
Gertler F B
Cooper J A
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.19.7.5179
Published
1999-07-00
Pages
5179-88
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC84361
Subset
IM
Grants
NCI NIH HHS · R01 CA041072 · United States
NIGMS NIH HHS · R01 GM058801 · United States
NIGMS NIH HHS · GM58801-01 · United States
NCI NIH HHS · R01-CA-41072 · United States
External Links
PubMed source DOI: 10.1128/MCB.19.7.5179 PMC Full Text View journal details
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