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Alteration of Neuropilin‑1 and Heparan Sulfate Interaction Impairs Murine B16 Tumor Growth
- Painter, Chelsea D;
- Sankaranarayanan, Nehru Viji;
- Nagarajan, Balaji;
- Clausen, Thomas Mandel;
- West, Alan MV;
- Setiawan, Nicollette J;
- Park, Jeeyoung;
- Porell, Ryan N;
- Bartels, Phillip L;
- Sandoval, Daniel R;
- Vasquez, Gabriel J;
- Chute, John P;
- Godula, Kamil;
- Vander Kooi, Craig W;
- Gordts, Philip LSM;
- Corbett, Kevin D;
- Termini, Christina M;
- Desai, Umesh R;
- Esko, Jeffrey D
- et al.
Published Web Location
https://doi.org/10.1021/acschembio.4c00389Abstract
Neuropilin-1 acts as a coreceptor with vascular endothelial growth factor receptors to facilitate binding of its ligand, vascular endothelial growth factor. Neuropilin-1 also binds to heparan sulfate, but the functional significance of this interaction has not been established. A combinatorial library screening using heparin oligosaccharides followed by molecular dynamics simulations of a heparin tetradecasaccharide suggested a highly conserved binding site composed of amino acid residues extending across the b1 and b2 domains of murine neuropilin-1. Mutagenesis studies established the importance of arginine513 and lysine514 for binding of heparin to a recombinant form of Nrp1 composed of the a1, a2, b1, and b2 domains. Recombinant Nrp1 protein bearing R513A,K514A mutations showed a significant loss of heparin-binding, heparin-induced dimerization, and heparin-dependent thermal stabilization. Isothermal calorimetry experiments suggested a 1:2 complex of heparin tetradecasaccharide:Nrp1. To study the impact of altered heparin binding in vivo, a mutant allele of Nrp1 bearing the R513A,K514A mutations was created in mice (Nrp1D) and crossbred to Nrp1+/- mice to examine the impact of altered heparan sulfate binding. Analysis of tumor formation showed variable effects on tumor growth in Nrp1D/D mice, resulting in a frank reduction in tumor growth in Nrp1D/- mice. Expression of mutant Nrp1D protein was normal in tissues, suggesting that the reduction in tumor growth was due to the altered binding of heparin/heparan sulfate to neuropilin-1. These findings suggest that the interaction of neuropilin-1 with heparan sulfate modulates its stability and its role in tumor formation and growth.
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