Inhibitory Peptides of the Sulfotransferase Domain of the Heparan Sulfate Enzyme, N-Deacetylase-N-sulfotransferase-1
| Autor: | Maria A. Juliano, Jeffrey D. Esko, Tarsis F. Gesteira, Ivarne L.S. Tersariol, Helena B. Nader, Alessandro Taunay-Rodrigues, Wadih Arap, Vivien Jane Coulson-Thomas, Renata Pasqualini, Vitor Oliveira, Bryan E. Thacker, Maria Aparecida da Silva Pinhal |
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| Přispěvatelé: | Universidade Federal de São Paulo (UNIFESP), Univ Texas MD Anderson Canc Ctr, Univ Mogi das Cruzes, Univ Calif San Diego |
| Rok vydání: | 2011 |
| Předmět: |
Sulfotransferase
Phage display Amino Acid Motifs Glycobiology and Extracellular Matrices Peptide CHO Cells Peptides Cyclic Biochemistry Mice chemistry.chemical_compound Cricetulus Sulfation Peptide Library Cricetinae Animals Humans Enzyme Inhibitors Molecular Biology Heparan Sulfate Biosynthesis chemistry.chemical_classification biology Active site Cell Biology Heparan sulfate Molecular biology Protein Structure Tertiary Amino acid chemistry biology.protein Heparitin Sulfate Sulfotransferases |
| Zdroj: | Repositório Institucional da UNIFESP Universidade Federal de São Paulo (UNIFESP) instacron:UNIFESP |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m110.100719 |
| Popis: | 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. Universidade Federal de São Paulo, Dept Bioquim, BR-04044020 São Paulo, Brazil Universidade Federal de São Paulo, Dept Biofis, BR-04044020 São Paulo, Brazil Univ Texas MD Anderson Canc Ctr, David H Koch Ctr, Houston, TX 77030 USA Univ Mogi das Cruzes, Ctr Interdisciplinar Invest Bioquim, BR-05508000 São Paulo, Brazil Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA Univ Calif San Diego, Biomed Sci Grad Program, San Diego, CA USA Universidade Federal de São Paulo, Dept Bioquim, BR-04044020 São Paulo, Brazil Universidade Federal de São Paulo, Dept Biofis, BR-04044020 São Paulo, Brazil Web of Science |
| Databáze: | OpenAIRE |
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