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The matrix polysaccharide hyaluronan (HA) has a critical role in the expansion of the cumulus cell-oocyte complex (COC), a process that is necessary for ovulation and fertilization in most mammals. Hyaluronan is organized into a crosslinked network by the cooperative action of three proteins, inter-alpha-inhibitor (IalphaI), pentraxin-3 and TNF-induced protein-6 (TSG-6), driving the expansion of the COC and providing the cumulus matrix with its required viscoelastic properties. While it is known that matrix stabilization involves the TSG-6-mediated transfer of IalphaI heavy chains (HC) onto hyaluronan (to form covalent HC-HA complexes that are crosslinked by pentraxin-3), and that this occurs via the formation of covalent HC-TSG-6 intermediates, the underlying molecular mechanisms are not well understood. Here, we have determined the tertiary structure of the CUB module from human TSG-6, identifying a calcium ion-binding site and chelating glutamic acid residue that mediate the formation of HC-TSG-6. This occurs via an initial metal ion-dependent, non-covalent, interaction between TSG-6 and HCs that also requires the presence of a HC-associated magnesium ion. In addition, we have found that the well-characterised hyaluronan-binding site in the TSG-6 Link module is not used for recognition during transfer of HCs onto HA. Analysis of TSG-6 mutants (with either impaired transferase and/or hyaluronan-binding functions), revealed that while the TSG-6-mediated formation of HC-HA complexes is essential for the expansion of mouse COCs in vitro, the hyaluronan-binding function of TSG-6 does not play a major role in the stabilization of the murine cumulus matrix.
Originalsprog | Engelsk |
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Tidsskrift | Journal of Biological Chemistry |
Vol/bind | 290 |
Sider (fra-til) | 28708-28723 |
Antal sider | 16 |
ISSN | 0021-9258 |
DOI | |
Status | Udgivet - 27 nov. 2015 |
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