Human extracellular sulfatases use a dual mechanism for regulation of growth factor interactions with heparan sulfate proteoglycans.

Cells rely on extracellular signals such as growth factors (GFs) to mediate critical biological functions. Membrane-associated proteins bearing negatively charged heparan sulfate (HS) sugar chains engage with GFs and present them to their receptors, which regulates their activity. Two extracellular sulfatase (Sulf) enzymes can edit HS and alter GF interactions and activity, although the precise mechanisms remain unclear. By using chemically defined HS-mimetics as probes, we have discovered that Sulfs can modulate HS by means of catalytic alterations and competitive blocking of GF-binding sites. These unique dual activities distinguish Sulfs from other enzymes and provide clues to their roles in development and disease.