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Originally published In Press as doi:10.1074/jbc.M414343200 on February 17, 2005

J. Biol. Chem., Vol. 280, Issue 18, 18189-18201, May 6, 2005
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Towards a Structure for a TSG-6·Hyaluronan Complex by Modeling and NMR Spectroscopy

INSIGHTS INTO OTHER MEMBERS OF THE LINK MODULE SUPERFAMILY*{boxs}

Charles D. Blundell{ddagger}§, Andrew Almond§, David J. Mahoney{ddagger}§, Paul L. DeAngelis||**, Iain D. Campbell§{ddagger}{ddagger}, and Anthony J. Day, Supported by the Medical Research Council{ddagger}§§§

From the {ddagger}Medical Research Council Immunochemistry Unit and the §Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom and the ||Department of Biochemistry and Molecular Biology, Oklahoma Center for Medical Glycobiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 63104

The Link module from human TSG-6, a hyaladherin with roles in ovulation and inflammation, has a hyaluronan (HA)-binding groove containing two adjacent tyrosine residues that are likely to form CH-{pi} stacking interactions with sequential rings in the sugar. We have used this observation to construct a model of a protein·HA complex, which was then tested against existing experimental information and by acquisition of new NMR data sets of [13C, 15N]HA (8-mer) complexed with unlabeled protein. A major finding of this analysis was that acetamido side chains of two GlcNAc rings fit into hydrophobic pockets on either side of the adjacent tyrosines, providing a selectivity mechanism of HA over other polysaccharides. Furthermore, two basic residues have a separation that matches that of glucuronic acids in the sugar, consistent with the formation of salt bridges; NMR experiments at a range of pH values identified protein groups that titrate due to their proximity to a free carboxylate in HA. Sequence alignment and construction of homology models for all human Link modules in their HA-bound states revealed that many of these features are conserved across the superfamily, thus allowing the prediction of functionally important residues. In the case of cartilage link protein, its two Link modules were docked together (using bound HA as a guide), identifying hydrophobic residues likely to form an intra-Link module interface as well as amino acids that could be involved in supporting intermolecular interactions between link proteins and chondroitin sulfate proteoglycans. Here, we propose a mechanism for ternary complex formation that generates higher order helical structures, as may exist in cartilage aggregates.

Received for publication, December 21, 2004 , and in revised form, February 7, 2005.

The chemical shift data reported in this paper have been submitted to BioMagResBank with accession number(s) 6392 and 6393.

* This work was supported in part by Arthritis Research Campaign Grants D0569, 14871, and M0625. 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.

{boxs} The on-line version of this article (available at http://www.jbc.org) contains Supplemental Figs. 1 and 2 and Supplemental Tables 1 and 2.

Supported by a Biotechnology and Biological Sciences Research Council Sir David Phillips research fellowship.

** Supported by National Science Foundation Grant MCB-9876193.

{ddagger}{ddagger} Suported by the Wellcome Trust and the Biotechnology and Biological Sciences Research Council.

§§ To whom correspondence should be addressed: MRC Immunochemistry Unit, Dept. of Biochemistry, University of Oxford, South Parks Rd., Oxford OX1 3QU, UK. Tel.: 44-1865-275-349; Fax: 44-1865-275-729; E-mail: tony.day{at}bioch.ox.ac.uk.


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