Structure of Pleiotrophin- and Hepatocyte Growth Factor-binding Sulfated Hexasaccharide Determined by Biochemical and Computational Approaches

Li Fuchuan; Nandini Chilkunda D.; Hattori Tomohide; Bao Xingfeng; Murayama Daisuke; Nakamura Toshikazu; Fukushima Nobuhiro; Sugahara Kazuyuki

タイトル	en Structure of Pleiotrophin- and Hepatocyte Growth Factor-binding Sulfated Hexasaccharide Determined by Biochemical and Computational Approaches
作成者	en Li, Fuchuan en Nandini, Chilkunda D. en Hattori, Tomohide en Bao, Xingfeng en Murayama, Daisuke en Nakamura, Toshikazu en Fukushima, Nobuhiro en Sugahara, Kazuyuki NRID 1000060154449
アクセス権	open access
主題	NDC 460
内容注記	Abstract en Endogenous pleiotrophin and hepatocyte growth factor (HGF) mediate the neurite outgrowth-promoting activity of chondroitin sulfate (CS)/dermatan sulfate (DS) hybrid chains isolated from embryonic pig brain. CS/DS hybrid chains isolated from shark skin have a different disaccharide composition, but also display these activities. In this study, pleiotrophin- and HGF-binding domains in shark skin CS/DS were investigated. A high-affinity CS/DS fraction was isolated using a pleiotrophin-immobilized column. It showed marked neurite outgrowth-promoting activity and strong inhibitory activity against the binding of pleiotrophin to immobilized CS/DS chains from embryonic pig brain. The inhibitory activity was abolished by chondroitinase ABC or B, and partially reduced by chondroitinase AC-I. A pentasulfated hexasaccharide with a novel structure was isolated from the chondroitinase AC-I digest using pleiotrophin-affinity and anion-exchange chromatographies. It displayed a potent inhibitory effect on the binding of HGF to immobilized shark skin CS/DS chains, suggesting that the pleiotrophin- and HGF-binding domains at least partially overlap in the CS/DS chains involved in the neuritogenic activity. Computational chemistry using molecular modeling and calculations of the electrostatic potential of the hexasaccharide and two pleiotrophin-binding octasaccharides previously isolated from CS/DS hybrid chains of embryonic pig brain identified an electronegative zone potentially involved in the molecular recognition of the oligosaccharides by pleiotrophin. Homology modeling of pleiotrophin based on a related midkine protein structure predicted the binding pocket of pleiotrophin for the oligosaccharides and provided new insights into the molecular mechanism of the interactions between the oligosaccharides and pleiotrophin.
日付	Issued2010-09-03
言語	eng
資源タイプ	journal article
出版タイプ	AM
資源識別子	HDL http://hdl.handle.net/2115/44207
関連	isVersionOf DOI https://doi.org/10.1074/jbc.M110.118703 PMID 20584902
収録誌情報	PISSN 0021-9258 en Journal of Biological Chemistry 巻285 号36 開始ページ27673 終了ページ27685
ファイル	fulltext revisedtextLisubmitted100605MZ.pdf 1.99 MB (application/pdf) Issued2010-09-03
コンテンツ更新日時	2023-07-26