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Sci Rep. 2017 Apr 26;7(1):1210. doi: 10.1038/s41598-017-01264-8.

Sulfated Hyaluronan Derivatives Modulate TGF-β1:Receptor Complex Formation: Possible Consequences for TGF-β1 Signaling.

Author information

1
Institute of Materials Science, Max Bergmann Center of Biomaterials, TU Dresden, Budapester Straße 27, 01069, Dresden, Germany.
2
Structural Bioinformatics, BIOTEC TU Dresden, Tatzberg 47-51, 01307, Dresden, Germany.
3
Medical Department, Institute of Physiological Chemistry, TU Dresden, Fiedlerstraße 42, 01307, Dresden, Germany.
4
Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Straße 2+4, 14195, Berlin, Germany.
5
Biomaterials Department, INNOVENT e.V., Prüssingstraße 27 B, 07745, Jena, Germany.
6
Institute of Materials Science, Max Bergmann Center of Biomaterials, TU Dresden, Budapester Straße 27, 01069, Dresden, Germany. Vera.Hintze@tu-dresden.de.

Abstract

Glycosaminoglycans are known to bind biological mediators thereby modulating their biological activity. Sulfated hyaluronans (sHA) were reported to strongly interact with transforming growth factor (TGF)-β1 leading to impaired bioactivity in fibroblasts. The underlying mechanism is not fully elucidated yet. Examining the interaction of all components of the TGF-β1:receptor complex with sHA by surface plasmon resonance, we could show that highly sulfated HA (sHA3) blocks binding of TGF-β1 to its TGF-β receptor-I (TβR-I) and -II (TβR-II). However, sequential addition of sHA3 to the TβR-II/TGF-β1 complex led to a significantly stronger recruitment of TβR-I compared to a complex lacking sHA3, indicating that the order of binding events is very important. Molecular modeling suggested a possible molecular mechanism in which sHA3 could potentially favor the association of TβR-I when added sequentially. For the first time bioactivity of TGF-β1 in conjunction with sHA was investigated at the receptor level. TβR-I and, furthermore, Smad2 phosphorylation were decreased in the presence of sHA3 indicating the formation of an inactive signaling complex. The results contribute to an improved understanding of the interference of sHA3 with TGF-β1:receptor complex formation and will help to further improve the design of functional biomaterials that interfere with TGF-β1-driven skin fibrosis.

PMID:
28446792
PMCID:
PMC5430790
DOI:
10.1038/s41598-017-01264-8
[Indexed for MEDLINE]
Free PMC Article

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