title: HSulf sulfatases catalyze processive and oriented 6-O-desulfation of heparan sulfate that differentially regulates fibroblast growth factor activity.
abstract: 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.
authors: 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.
authors: Amal
authors: A
authors: Seffouh
authors: Fabian
authors: F
authors: Milz
authors: Cédric
authors: C
authors: Przybylski
authors: Cédric
authors: C
authors: Laguri
authors: Arie
authors: A
authors: Oosterhof
authors: Sébastien
authors: S
authors: Bourcier
authors: Rabia
authors: R
authors: Sadir
authors: Elodie
authors: E
authors: Dutkowski
authors: Régis
authors: R
authors: Daniel
authors: Toin H
authors: TH
authors: van Kuppevelt
authors: Thomas
authors: T
authors: Dierks
authors: Hugues
authors: H
authors: Lortat-Jacob
authors: Romain R
authors: RR
authors: Vivès
mesh_terms: D002384:Catalysis; D002460:Cell Line; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006497:Heparan Sulfate / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D009844:Oligosaccharides / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013379:Substrate Specificity; D013429:Sulfatases; D015238:Sulfotransferases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2; D006497:Heparan Sulfate; D009844:Oligosaccharides; D011994:Recombinant Proteins; D013429:Sulfatases; D015238:Sulfotransferases; C470791:SULF1 protein, human; C470792:SULF2 protein, human
keywords: enzymatic mechanism; glycosaminoglycan; interaction; proteoglycan; structure/function relationships