HSulf sulfatases catalyze processive and oriented 6-O-desulfation of heparan sulfate that differentially regulates fibroblast growth factor activity.

Institut de Biologie Structurale Jean-Pierre Ebel, Unité Mixte de Recherche 5075, Centre National de la Recherche Scientifique-Commissariat à l'Énergie Atomique et aux Énergies Alternatives-Université Joseph Fourier, Grenoble, France.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2013 Jun

filter terms:

Sulfs are extracellular sulfatases that have emerged recently as critical regulators of heparan sulfate (HS) activities through their ability to catalyze specific 6-O-desulfation of the polysaccharide. Consequently, Sulfs have been involved in many physiological and pathological processes, and notably for Sulf-2, in the development of cancers with poor prognosis. Despite growing interest, little is known about the structure and activity of these enzymes and the way they induce dynamic remodeling of HS 6-O-sulfation status. Here, we have combined an array of analytical approaches, including mass spectrometry, NMR, HS oligosaccharide sequencing, and FACS, to dissect HSulf-2 sulfatase activity, either on a purified octasaccharide used as a mimic of HS functional domains, or on intact cell-surface HS chains. In parallel, we have studied the functional consequences of HSulf-2 activity on fibroblast growth factor (FGF)-induced mitogenesis and found that the enzyme could differentially regulate FGF1 and FGF2 activities. Notably, these data supported the existence of precise 6-O-sulfation patterns for FGF activation and provided new insights into the saccharide structures involved. Altogether, our data bring to light an original processive enzymatic mechanism, by which HSulfs catalyze oriented alteration of HS 6-O-desulfation patterns and direct fine and differential regulation of HS functions.

Citation

Amal Seffouh, Fabian Milz, Cédric Przybylski, Cédric Laguri, Arie Oosterhof, Sébastien Bourcier, Rabia Sadir, Elodie Dutkowski, Régis Daniel, Toin H van Kuppevelt, Thomas Dierks, Hugues Lortat-Jacob, Romain R Vivès. HSulf sulfatases catalyze processive and oriented 6-O-desulfation of heparan sulfate that differentially regulates fibroblast growth factor activity. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2013 Jun;27(6):2431-9