Human Sulfatases Use Dual Mechanisms to Control Growth Factor–Heparan Sulfate Interactions

Growth factor signaling governs essential cellular processes, and its precision relies on interactions with heparan sulfate on the cell surface. The sulfation pattern of heparan sulfate dictates its capacity to bind specific growth factors and their receptors, thereby controlling the signaling strength and specificity. Extracellular endosulfatases, including sulfatase 1 and sulfatase 2, further modulate these interactions by selectively removing sulfate groups from defined regions of heparan sulfate. Although these enzymes are known to influence developmental- and disease-related signaling, their direct effects on growth factor recognition have remained unclear. Using a panel of bioengineered heparan sulfate conjugates with defined sulfation compositions, this study examines how the structural features of heparan sulfate govern its regulation by the sulfatases. By tracking enzyme binding and catalytic remodeling, we found that both enzymes rely on two coordinated mechanisms: catalytic desulfation of heparan sulfate and competitive binding that transiently prevents growth factor association. The balance between catalytic remodeling and competitive binding depends on the sulfation characteristics of the heparan sulfate substrate and the identity of the growth factor and differs between the two enzyme isoforms. These findings provide a new framework for understanding how extracellular sulfatases shape growth factor signaling in both development and disease.