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J. Biol. Chem., Vol. 280, Issue 42, 35318-35328, October 21, 2005

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Demonstration of the Pleiotrophin-binding Oligosaccharide Sequences Isolated from Chondroitin Sulfate/Dermatan Sulfate Hybrid Chains of Embryonic Pig Brains^*

Xingfeng Bao1, Takashi Muramatsu2, and Kazuyuki Sugahara, Supported by the Core Research for Evolutional Science and Technology of the Japan Science and Technology Agency3

From the Department of Biochemistry, Kobe Pharmaceutical Univeristy, 4-19-1, Motoyama-kita-machi, Higashinada-ku, Kobe 658-8558 and the Department of Biochemistry, Nagoya University School of Medicine, Nagoya 466-8550, Japan

Mammalian brains contain significant amounts of chondroitin sulfate (CS), dermatan sulfate (DS), and CS/DS hybrid chains. CS/DS chains isolated from embryonic pig brains (E-CS/DS) promote the outgrowth of neurites in embryonic mouse hippocampal neurons in culture by interacting with pleiotrophin (PTN), a heparin-binding growth factor. Here, we analyzed oligosaccharides isolated from E-CS/DS, which showed that octasaccharides were the minimal size capable of interacting with PTN at a physiological salt concentration. Five and eight sequences were purified from fluorescently labeled PTN-bound and -unbound octasaccharide fractions, respectively, by enzymatic digestion followed by PTN-affinity chromatography. Their sequences were determined by enzymatic digestion in conjunction with high performance liquid chromatography, revealing a critical role for oversulfated D and/or iD disaccharides in the low yet significant affinity for PTN, which is required for neuritogenesis. The critical D and iD units are GlcUA(2-O-sulfate)1-3GalNAc(6-O-sulfate) and IdoUA(2-O-sulfate)1-3GalNAc(6-O-sulfate), respectively, where IdoUA represents L-iduronic acid. In contrast, high affinity interactions with PTN required decasaccharides with E units (GlcUA1-3GalNAc(4, 6-O-disulfate)), B units (GlcUA(2-O-sulfate)1-3GalNAc(4-O-sulfate)), and/or their IdoUA-containing counterparts (iE and iB) in addition to D/iD units, although the biological significance of such strong interactions remains to be investigated. Thus, chain size and composition are crucial to the interaction with PTN, and PTN binds to multiple sequences in E-CS/DS chains with distinct affinity. Notably, not only heparan sulfate but also CS/DS hybrid chain structures of mammalian brains contain a high degree of microheterogeneity with a cluster of oversulfated disaccharides and appear to play roles in regulating the functions of PTN.

Received for publication, July 6, 2005 , and in revised form, August 23, 2005.

^* The work performed in Kobe was supported in part by HAITEKU (2004-2008) from the Japan Private School Promotion Foundation and Grants-in-Aid for Exploratory Research 17659020, Scientific Research-B 16390026, and Scientific Research on Priority Areas 14082207 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table SI.

¹ Supported by postdoctoral fellowship HAITEKU (2004-2008) from the Japan Private School Promotion Foundation.

² Present address: Dept. of Health Sciences, Faculty of Psychological and Physical Sciences, Aichi Gakuin University, Nisshin 470-0915, Japan.

³ To whom correspondence should be addressed: Tel.: 81-78-441-7570; Fax: 81-78-441-7569; E-mail: k-sugar{at}kobepharma-u.ac.jp.

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