Hepatocyte　growth　factor/scatter　factor　(HGF/SF)　has　a　cofactor　requirement　for　heparan　sulfate　(HS)　and　dermatan　sulfate　(DS)　in　the　optimal　activation　of　its　signaling　receptor　MET.　However,　these　two　glycosaminoglycans　(GAGs)　have　different　sugar　backbones　and　sulfation　patterns,　with　only　the　presence　of　iduronate　in　common.　The　structural　basis　for　GAG　recognition　and　activation　is　thus　very　unclear.　We　have　clarified　this　by　testing　a　wide　array　of　natural　and　modified　GAGs　for　both　protein　binding　and　activation.　Comparisons　between　Ascidia　nigra　(2,6-O-sulfated)　and　mammalian　(mainly　4-O-sulfated)　DS　species,　as　well　as　between　a　panel　of　specifically　desulfated　heparins,　revealed　that　no　specific　sulfate　isomer,　in　either　GAG,　is　vital　for　interaction　and　activity.　Moreover,　different　GAGs　of　similar　sulfate　density　had　comparable　properties,　although　affinity　and　potency　notably　increase　with　increasing　sulfate　density.　The　weaker　interaction　with　CS-E,　compared　with　DS,　shows　that　GlcA-containing　polymers　can　bind,　if　highly　sulfated,　but　emphasizes　the　importance　of　the　flexible　IdoA　ring.　Our　data　indicate　that　the　preferred　binding　sites　in　DS　in　vivo　will　be　comprised　of　disulfated,　IdoA(2S)-containing　motifs.　In　HS,　clustering　of　N-/2-O-/6-O-sulfation　in　S-domains　will　lead　to　strong　reactivity,　although　binding　can　also　be　mediated　by　the　transition　zones　where　sulfates　are　mainly　at　the　N-　and　6-O-　positions.　GAG　recognition　of　HGF/SF　thus　appears　to　be　primarily　driven　by　electrostatic　interactions　and　exhibits　an　interesting　interplay　between　requirements　for　iduronate　and　sulfate　density　that　may　reflect　in　part　a　preference　for　particular　sugar　chain　conformations.　©　2008　by　The　American　Society　for　Biochemistry　and　Molecular　Biology,　Inc.