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J. Biol. Chem., Vol. 279, Issue 26, 27239-27245, June 25, 2004
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From the
Cancer Research UK and University of Manchester, Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX and the ¶School of Biological Sciences, 1.800 Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom
Elucidation of the molecular structure of heparan sulfate (HS) is the key to understanding its functional versatility as a co-receptor for growth factors and morphogens. We have identified and exploited the novel substrate specificity of the coliphage K5 lyase in studies of the domain organization of HS. We show that K5 lyase cleaves HS principally within non-sulfated sequences of four or more N-acetylated disaccharides. Uniquely, sections comprising alternating N-acetylated and N-sulfated units are resistant to the enzyme, as are the highly sulfated S domains. Spacing of the K5 lyase cleavage sites (
7–8 kDa) is similar to that of the S domains. On the basis of these findings, we propose a refined model of the structure of HS in which N-acetylated sequences of four to five disaccharide units (GlcNAc-GlcUA)4–5 are positioned centrally between the S domains. The latter are embedded within N-acetylated and N-sulfated sequences, forming extended regions of hypervariable sulfation distributed at regular intervals along the polymer chain. K5 lyase provides a means of excision of these composite sulfated regions for structural and functional analyses.
Received for publication, February 18, 2004 , and in revised form, March 24, 2004.
* This work was funded by grants from Cancer Research UK, Matrix Therapeutics, and the Biotechnology and Biological Sciences Research Council. 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.
Present address: The School of Applied Sciences, University of Huddersfield, Huddersfield HD1 3DH, UK.
|| To whom correspondence should be addressed. E-mail: cmerry{at}picr.man.ac.uk.
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