Alteration of Neuropilin-1 and Heparan Sulfate Interaction Impairs Murine B16 Tumor Growth.

Autor:	Painter CD; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093, United States.; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California 92093, United States., Sankaranarayanan NV; Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia 23298, United States.; Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, Virginia 23219, United States., Nagarajan B; Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia 23298, United States.; Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, Virginia 23219, United States., Mandel Clausen T; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093, United States.; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California 92093, United States., West AMV; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093, United States., Setiawan NJ; Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington 98109, United States., Park J; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093, United States., Porell RN; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California 92093, United States.; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, United States., Bartels PL; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California 92093, United States.; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, United States., Sandoval DR; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093, United States.; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California 92093, United States., Vasquez GJ; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093, United States., Chute JP; Samuel Oschin Cancer Center, Cedars Sinai Medical Center, Los Angeles, California 90048, United States.; Division of Hematology & Cellular Therapy, Cedars Sinai Medical Center, Los Angeles, California 90048, United States.; Regenerative Medicine Institute, Cedars Sinai Medical Center, Los Angeles, California 90048, United States., Godula K; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California 92093, United States.; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, United States., Vander Kooi CW; Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida 32610, United States., Gordts PLSM; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California 92093, United States.; Department of Medicine, University of California, San Diego, La Jolla, California 92093, United States., Corbett KD; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093, United States.; Department of Molecular Biology, University of California, San Diego, La Jolla, California 92093, United States., Termini CM; Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington 98109, United States., Desai UR; Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia 23298, United States.; Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, Virginia 23219, United States., Esko JD; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093, United States.; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California 92093, United States.
Jazyk:	angličtina
Zdroj:	ACS chemical biology [ACS Chem Biol] 2024 Aug 16; Vol. 19 (8), pp. 1820-1835. Date of Electronic Publication: 2024 Aug 04.
DOI:	10.1021/acschembio.4c00389
Abstrakt:	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 ( Nrp1 D ) 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 Nrp1 D/D mice, resulting in a frank reduction in tumor growth in Nrp1 D/- mice. Expression of mutant Nrp1 D 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.
Databáze:	MEDLINE
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