Inhibitory peptides of the sulfotransferase domain of the heparan sulfate enzyme, N-Deacetylase-N-sulfotransferase-1

Tarsis F. Gesteira, Vivien J. Coulson-Thomas, Alessandro Taunay-Rodrigues, Vitor Oliveira, Bryan E. Thacker, Maria A. Juliano, Renata Pasqualini, Wadih Arap, Ivarne L.S. Tersariol, Helena B. Nader, Jeffrey D. Esko, Maria A.S. Pinhal

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

N-Deacetylase-N-sulfotransferase 1 (Ndst1) catalyzes the initial modification of heparan sulfate and heparin during their biosynthesis by removal of acetyl groups from subsets of N-acetylglucosamine units and subsequent sulfation of the resulting free amino groups. In this study, we used a phage display library to select peptides that interact with Ndst1, with the aim of finding inhibitors of the enzyme. The phage library consisted of cyclic random 10-mer peptides expressed in the phage capsid protein pIII. Selection was based on the ability of engineered phage to bind to recombinant murine Ndst1 (mNdst1) and displacement with heparin. Peptides that were enriched through multiple cycles of binding and disassociation displayed two specific sequences, CRGWRGEKIGNC and CNMQALSMPVTC. Both peptides inhibited mNdst1 activity in vitro, however, by distinct mechanisms. The peptide CRGWRGEKIGNC presents a chemokine-like repeat motif (BXX, where B represents a basic amino acid and X is a noncharged amino acid) and binds to heparan sulfate, thus blocking the binding of substrate to the enzyme. The peptide NMQALSMPVT inhibits mNdst1 activity by direct interaction with the enzyme near the active site. The discovery of inhibitory peptides in this way suggests a method for developing peptide inhibitors of heparan sulfate biosynthesis.

Original languageEnglish (US)
Pages (from-to)5338-5346
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number7
DOIs
StatePublished - Feb 18 2011

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Sulfotransferases
Heparitin Sulfate
Peptides
Bacteriophages
Enzymes
Biosynthesis
Heparin
Basic Amino Acids
Acetylglucosamine
heparitin sulfotransferase
Protein Domains
Capsid Proteins
Enzyme Inhibitors
Chemokines
Libraries
Catalytic Domain
Display devices
Amino Acids
Substrates

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Gesteira, T. F., Coulson-Thomas, V. J., Taunay-Rodrigues, A., Oliveira, V., Thacker, B. E., Juliano, M. A., ... Pinhal, M. A. S. (2011). Inhibitory peptides of the sulfotransferase domain of the heparan sulfate enzyme, N-Deacetylase-N-sulfotransferase-1. Journal of Biological Chemistry, 286(7), 5338-5346. https://doi.org/10.1074/jbc.M110.100719
Gesteira, Tarsis F. ; Coulson-Thomas, Vivien J. ; Taunay-Rodrigues, Alessandro ; Oliveira, Vitor ; Thacker, Bryan E. ; Juliano, Maria A. ; Pasqualini, Renata ; Arap, Wadih ; Tersariol, Ivarne L.S. ; Nader, Helena B. ; Esko, Jeffrey D. ; Pinhal, Maria A.S. / Inhibitory peptides of the sulfotransferase domain of the heparan sulfate enzyme, N-Deacetylase-N-sulfotransferase-1. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 7. pp. 5338-5346.
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abstract = "N-Deacetylase-N-sulfotransferase 1 (Ndst1) catalyzes the initial modification of heparan sulfate and heparin during their biosynthesis by removal of acetyl groups from subsets of N-acetylglucosamine units and subsequent sulfation of the resulting free amino groups. In this study, we used a phage display library to select peptides that interact with Ndst1, with the aim of finding inhibitors of the enzyme. The phage library consisted of cyclic random 10-mer peptides expressed in the phage capsid protein pIII. Selection was based on the ability of engineered phage to bind to recombinant murine Ndst1 (mNdst1) and displacement with heparin. Peptides that were enriched through multiple cycles of binding and disassociation displayed two specific sequences, CRGWRGEKIGNC and CNMQALSMPVTC. Both peptides inhibited mNdst1 activity in vitro, however, by distinct mechanisms. The peptide CRGWRGEKIGNC presents a chemokine-like repeat motif (BXX, where B represents a basic amino acid and X is a noncharged amino acid) and binds to heparan sulfate, thus blocking the binding of substrate to the enzyme. The peptide NMQALSMPVT inhibits mNdst1 activity by direct interaction with the enzyme near the active site. The discovery of inhibitory peptides in this way suggests a method for developing peptide inhibitors of heparan sulfate biosynthesis.",
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Gesteira, TF, Coulson-Thomas, VJ, Taunay-Rodrigues, A, Oliveira, V, Thacker, BE, Juliano, MA, Pasqualini, R, Arap, W, Tersariol, ILS, Nader, HB, Esko, JD & Pinhal, MAS 2011, 'Inhibitory peptides of the sulfotransferase domain of the heparan sulfate enzyme, N-Deacetylase-N-sulfotransferase-1', Journal of Biological Chemistry, vol. 286, no. 7, pp. 5338-5346. https://doi.org/10.1074/jbc.M110.100719

Inhibitory peptides of the sulfotransferase domain of the heparan sulfate enzyme, N-Deacetylase-N-sulfotransferase-1. / Gesteira, Tarsis F.; Coulson-Thomas, Vivien J.; Taunay-Rodrigues, Alessandro; Oliveira, Vitor; Thacker, Bryan E.; Juliano, Maria A.; Pasqualini, Renata; Arap, Wadih; Tersariol, Ivarne L.S.; Nader, Helena B.; Esko, Jeffrey D.; Pinhal, Maria A.S.

In: Journal of Biological Chemistry, Vol. 286, No. 7, 18.02.2011, p. 5338-5346.

Research output: Contribution to journalArticle

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T1 - Inhibitory peptides of the sulfotransferase domain of the heparan sulfate enzyme, N-Deacetylase-N-sulfotransferase-1

AU - Gesteira, Tarsis F.

AU - Coulson-Thomas, Vivien J.

AU - Taunay-Rodrigues, Alessandro

AU - Oliveira, Vitor

AU - Thacker, Bryan E.

AU - Juliano, Maria A.

AU - Pasqualini, Renata

AU - Arap, Wadih

AU - Tersariol, Ivarne L.S.

AU - Nader, Helena B.

AU - Esko, Jeffrey D.

AU - Pinhal, Maria A.S.

PY - 2011/2/18

Y1 - 2011/2/18

N2 - N-Deacetylase-N-sulfotransferase 1 (Ndst1) catalyzes the initial modification of heparan sulfate and heparin during their biosynthesis by removal of acetyl groups from subsets of N-acetylglucosamine units and subsequent sulfation of the resulting free amino groups. In this study, we used a phage display library to select peptides that interact with Ndst1, with the aim of finding inhibitors of the enzyme. The phage library consisted of cyclic random 10-mer peptides expressed in the phage capsid protein pIII. Selection was based on the ability of engineered phage to bind to recombinant murine Ndst1 (mNdst1) and displacement with heparin. Peptides that were enriched through multiple cycles of binding and disassociation displayed two specific sequences, CRGWRGEKIGNC and CNMQALSMPVTC. Both peptides inhibited mNdst1 activity in vitro, however, by distinct mechanisms. The peptide CRGWRGEKIGNC presents a chemokine-like repeat motif (BXX, where B represents a basic amino acid and X is a noncharged amino acid) and binds to heparan sulfate, thus blocking the binding of substrate to the enzyme. The peptide NMQALSMPVT inhibits mNdst1 activity by direct interaction with the enzyme near the active site. The discovery of inhibitory peptides in this way suggests a method for developing peptide inhibitors of heparan sulfate biosynthesis.

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Gesteira TF, Coulson-Thomas VJ, Taunay-Rodrigues A, Oliveira V, Thacker BE, Juliano MA et al. Inhibitory peptides of the sulfotransferase domain of the heparan sulfate enzyme, N-Deacetylase-N-sulfotransferase-1. Journal of Biological Chemistry. 2011 Feb 18;286(7):5338-5346. https://doi.org/10.1074/jbc.M110.100719