title: Structure, sulfatide binding properties, and inhibition of platelet aggregation by a disabled-2 protein-derived peptide.
abstract: Disabled-2 (Dab2) targets membranes and triggers a wide range of biological events, including endocytosis and platelet aggregation. Dab2, through its phosphotyrosine-binding (PTB) domain, inhibits platelet aggregation by competing with fibrinogen for α(IIb)β(3) integrin receptor binding. We have recently shown that the N-terminal region, including the PTB domain (N-PTB), drives Dab2 to the platelet membrane surface by binding to sulfatides through two sulfatide-binding motifs, modulating the extent of platelet aggregation. The three-dimensional structure of a Dab2-derived peptide encompassing the sulfatide-binding motifs has been determined in dodecylphosphocholine micelles using NMR spectroscopy. Dab2 sulfatide-binding motif contains two helices when embedded in micelles, reversibly binds to sulfatides with moderate affinity, lies parallel to the micelle surface, and when added to a platelet mixture, reduces the number and size of sulfatide-induced aggregates. Overall, our findings identify and structurally characterize a minimal region in Dab2 that modulates platelet homotypic interactions, all of which provide the foundation for rational design of a new generation of anti-aggregatory low-molecular mass molecules for therapeutic purposes.
authors.affiliation: Protein Signaling Domains Laboratory, Department of Biological Sciences, Virginia Tech, 1981 Kraft Dr., Rm. 2007, Blacksburg, VA 24061, USA.
authors.forename: Shuyan
authors.initials: S
authors.lastname: Xiao
authors.forename: John J
authors.initials: JJ
authors.lastname: Charonko
authors.forename: Xiangping
authors.initials: X
authors.lastname: Fu
authors.forename: Alireza
authors.initials: A
authors.lastname: Salmanzadeh
authors.forename: Rafael V
authors.initials: RV
authors.lastname: Davalos
authors.forename: Pavlos P
authors.initials: PP
authors.lastname: Vlachos
authors.forename: Carla V
authors.initials: CV
authors.lastname: Finkielstein
authors.forename: Daniel G S
authors.initials: DG
authors.lastname: Capelluto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins; D001665:Binding Sites; D002942:Circular Dichroism; D006801:Humans; D008823:Micelles; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000737:chemistry; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013433:Sulfoglycosphingolipids / Q000737:chemistry* / Q000378:metabolism; D020349:Surface Plasmon Resonance; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C102885:DAB2 protein, human; D008823:Micelles; D010455:Peptides; D013433:Sulfoglycosphingolipids; D025521:Tumor Suppressor Proteins; D010767:Phosphorylcholine; C028810:dodecylphosphocholine