2LSW

Structure, sulfatide-binding properties, and inhibition of platelet aggregation by a Disabled-2-derived peptide

Summary for 2LSW

• Entry DOI: 10.2210/pdb2lsw/pdb
• NMR Information: BMRB: 18449
• Descriptor: Disabled homolog 2 (1 entity in total)
• Functional Keywords: platelet aggregation inhibitor, sulfatides, dodecylphosphocholine, blood clotting
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P98082
• Total number of polymer chains: 1
• Total formula weight: 4405.16

Authors

Xiao, S. (deposition date: 2012-05-08, release date: 2012-09-19, Last modification date: 2024-05-15)

Primary citation

Xiao, S.,Charonko, J.J.,Fu, X.,Salmanzadeh, A.,Davalos, R.V.,Vlachos, P.P.,Finkielstein, C.V.,Capelluto, D.G.
Structure, Sulfatide Binding Properties, and Inhibition of Platelet Aggregation by a Disabled-2 Protein-derived Peptide.
J.Biol.Chem., 287:37691-37702, 2012

PubMed 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.

PubMed: 22977233
DOI: 10.1074/jbc.M112.385609

Experimental method

SOLUTION NMR