Pentosan polysulfate increases affinity between ADAMTS-5 and TIMP-3 through formation of an electrostatically driven trimolecular complex

Troeberg, Linda ORCID: https://orcid.org/0000-0003-0939-4651, Mulloy, Barbara, Ghosh, Peter, Lee, Meng-Huee, Murphy, Gillian and Nagase, Hideaki (2012) Pentosan polysulfate increases affinity between ADAMTS-5 and TIMP-3 through formation of an electrostatically driven trimolecular complex. Biochemical Journal, 443 (1). pp. 307-315. ISSN 0264-6021

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Abstract

The semi-synthetic sulfated polysaccharide PPS (pentosan polysulfate) increases affinity between the aggrecan-degrading ADAMTSs (adamalysins with thrombospondin motifs) and their endogenous inhibitor, TIMP (tissue inhibitor of metalloproteinases)-3. In the present study we demonstrate that PPS mediates the formation of a high-affinity trimolecular complex with ADAMTS-5 and TIMP-3. A TIMP-3 mutant that lacks extracellular-matrix-binding ability was insensitive to this affinity increase, and truncated forms of ADAMTS-5 that lack the Sp (spacer) domain had reduced PPS-binding ability and sensitivity to the affinity increase. PPS molecules composed of 11 or more saccharide units were 100-fold more effective than those of eight saccharide units, indicating the involvement of extended or multiple protein-interaction sites. The formation of a high-affinity trimolecular complex was completely abolished in the presence of 0.4 M NaCl. These results suggest that PPS enhances the affinity between ADAMTS-5 and TIMP-3 by forming electrostatically driven trimolecular complexes under physiological conditions.

Item Type:	Article
Uncontrolled Keywords:	biosynthesis,adamts5 protein,amino acid substitution,chromatography, gel,hek293 cells,humans,isolation & purification,protein binding,protein structure, tertiary,biosynthesis,sequence deletion,chemistry,biosynthesis
Faculty \ School:	Faculty of Science > School of Biological Sciences
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Groups > Musculoskeletal Medicine Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Depositing User:	LivePure Connector
Date Deposited:	04 Jan 2019 12:30
Last Modified:	19 Oct 2023 02:20
URI:	https://ueaeprints.uea.ac.uk/id/eprint/69442
DOI:	10.1042/BJ20112159

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