TAILIEUCHUNG - Báo cáo khoa học: Cell surface adhesion of pregnancy-associated plasma protein-A is mediated by four clusters of basic residues located in its third and fourth CCP module

The metalloproteinase pregnancy-associated plasma pro-tein-A (PAPP-A) cleaves a subset of insulin-like growth factor binding proteins (IGFBP), which inhibit the activities of insulin-like growth factor (IGF). Through this proteolytic activity, PAPP-A is believed to regulate IGF bioavailability in several biological systems, including the human repro-ductive system and the cardiovascular system. PAPP-A adheres to mammalian cells by interactions with glycos-aminoglycan (GAG), thus targeting the proteolytic activity of PAPP-A to the cell surface. . | Eur. J. Biochem. 271 1525-1535 2004 FEBS 2004 doi Cell surface adhesion of pregnancy-associated plasma protein-A is mediated by four clusters of basic residues located in its third and fourth CCP module Kathrin Weyer1 Michael T. Overgaard1 Lisbeth S. Laursen1 Claus G. Nielsen1 Alexander Schmitz1 Michael Christiansen2 Lars Sottrup-Jensen1 Linda C. Giudice3 and Claus Oxvig1 1 Department of Molecular Biology Science Park University of Aarhus Denmark department of Clinical Biochemistry Statens Serum Institut Copenhagen S Denmark 3Department of Gynecology and Obstetriss StnnforU Univsrsity California UAA The metalloproteinase pregnancy-associated plasma pro-tein-A PAPP-A cleaves a subset of insulin-like growth factor binding proteins IGFBP which inhibit the activities of insulin-like growth factor IGF . Through this proteolytic activity PAPP-A is believed to regulate IGF bioavailability in several biological systems including the human reproductive system and the cardiovascular system. PAPP-A adheres to mammalian cells by interactions with glycosaminoglycan GAG thus targeting the proteolytic activity of PAPP-A to the cell surface. Based on site-directed mutagenesis we here delineate the PAPP-A GAG-binding site in the C-terminal modules CCP3 and CCP4. Using heparin affinity chromatography commonly employed in such studies we define three clusters of arginines and lysines of CCP3 which are important for the interaction of PAPP-A with heparin. In a model of PAPP-A CCP3-CCP4 basic residues of these sequence clusters form a contiguous patch located on one side of the structure. Binding to the unknown natural cell surface receptor of PAPP-A assessed by flow cytometry also depends on residues of these three basic clusters. However single or double residue substitutions generally have a modest effect on PAPP-A heparin binding assessed by chromatography but cell surface adhesion was critically reduced by several of these substitutions emphasizing

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