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Molecular basis of antiangiogenic thrombospondin-1 type 1 repeat domain interactions with CD36. Arterioscler Thromb Vasc Biol 2013 Jul;33(7):1655-62

Date

05/04/2013

Pubmed ID

23640500

Pubmed Central ID

PMC3737738

DOI

10.1161/ATVBAHA.113.301523

Scopus ID

2-s2.0-84879103346 (requires institutional sign-in at Scopus site)   36 Citations

Abstract

OBJECTIVE: Antiangiogenic activity of thrombospondin-1 and related proteins is mediated by interactions between thrombospondin type 1 repeat (TSR) domains and the CD36, LIMP-2, Emp sequence homology (CLESH) domain of the endothelial cell receptor CD36. We sought to characterize key molecular determinants of the interaction between thrombospondin-1 TSR domains and the CD36 CLESH domain.

APPROACH AND RESULTS: Recombinant thrombospondin-1 TSR2 and TSR(2,3) constructs inhibited microvascular endothelial cell migration, microvascular endothelial cell tube formation, and vessel sprouting in aortic ring assays. Interaction with CD36 CLESH decoy peptides negated these effects. Mutational analyses identified a cluster of residues that confer positive charge to the TSR2 surface and mediate interaction with CD36 CLESH. Antiangiogenic activity was significantly reduced by charge-neutralizing mutations of the Arg-Trp ladder in TSR2, but not TSR3. Additionally, I438 and K464 of TSR2 were shown to be required for CD36 CLESH binding to TSR2. A complementary acidic cluster within CD36 CLESH is also required for antiangiogenic activity.

CONCLUSIONS: Thrombospondin-1 interacts with CD36 CLESH through electrostatic interactions mediated by a positively charged TSR2 surface and multiple negatively charged CD36 CLESH residues. Two key residues serve as specificity determinants that identify other TSR domains that interact with CD36 CLESH.

Author List

Klenotic PA, Page RC, Li W, Amick J, Misra S, Silverstein RL

Author

Roy L. Silverstein MD Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Angiogenesis Inhibitors
Animals
Aorta
CD36 Antigens
Cell Movement
Cells, Cultured
Computer Simulation
Endothelial Cells
Human Umbilical Vein Endothelial Cells
Humans
Mice
Mice, Inbred C57BL
Models, Molecular
Molecular Sequence Data
Mutagenesis, Site-Directed
Neovascularization, Physiologic
Protein Binding
Protein Interaction Domains and Motifs
Protein Interaction Mapping
Recombinant Proteins
Surface Properties
Thrombospondin 1
Tissue Culture Techniques