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

Troeberg L, Mulloy B, Ghosh P, Lee MH, Murphy G, Nagase H · The Biochemical Journal

How PPS actually strengthens the body's own aggrecanase brake: it bridges ADAMTS-5 and TIMP-3 into a single high-affinity three-part complex, requiring the enzyme's spacer domain and the inhibitor's matrix-binding region. Chains of 11 or more sugar units were 100-fold more effective than 8-unit chains, and the whole effect collapsed in high salt, confirming it is electrostatic.

Population

Recombinant ADAMTS-5, TIMP-3 and PPS fractions of defined chain length

Intervention

PPS at varying saccharide lengths

Comparator

PPS-free enzyme-inhibitor pairs and truncated protein mutants

Limitations

Purified proteins in buffer, not cartilage; PPS's developer is among the authors; the chain-length dependence means the effect is a property of a particular size distribution, which commercial preparations differ in.