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• W2000800531 abstract "Proteins that belong to the fibroblast growth factor (FGF) family regulate proliferation, migration, and differentiation of many cell types. Several FGFs, including the prototype factors FGF-1 and FGF-2, depend on interactions with heparan sulfate (HS) proteoglycans for activity. We have assessed tissue-derived HS fragments for binding to FGF-1 and FGF-2 to identify the authentic saccharide motifs required for interactions. Sequence information on a range of N-sulfated HS octasaccharides spanning from low to high affinity for FGF-1 was obtained. All octasaccharides with high affinity for FGF-1 (≥0.5 m NaCl required for elution) contained an internal IdoUA(2-OSO3)-GlcNSO3(6-OSO3)-IdoUA(2-OSO3)-trisaccharide motif. Octasaccharides with a higher overall degree of sulfation but lacking the specific trisaccharide motif showed lower affinity for FGF-1. FGF-2 was shown to bind to a mono-O-sulfated HS 6-mer carrying a single internal IdoUA(2-OSO3)-unit. However, a di-O-sulfated -IdoUA(2-OSO3)-GlcNSO3-IdoUA(2-OSO3)-trisaccharide sequence within a HS 8-mer gave stronger binding. These findings show that not only the number but also the positions of individual sulfate groups determine affinity of HS for FGFs. Our findings support the notion that FGF-dependent processes can be modulatedin vivo by regulated expression of distinct HS sequences. Proteins that belong to the fibroblast growth factor (FGF) family regulate proliferation, migration, and differentiation of many cell types. Several FGFs, including the prototype factors FGF-1 and FGF-2, depend on interactions with heparan sulfate (HS) proteoglycans for activity. We have assessed tissue-derived HS fragments for binding to FGF-1 and FGF-2 to identify the authentic saccharide motifs required for interactions. Sequence information on a range of N-sulfated HS octasaccharides spanning from low to high affinity for FGF-1 was obtained. All octasaccharides with high affinity for FGF-1 (≥0.5 m NaCl required for elution) contained an internal IdoUA(2-OSO3)-GlcNSO3(6-OSO3)-IdoUA(2-OSO3)-trisaccharide motif. Octasaccharides with a higher overall degree of sulfation but lacking the specific trisaccharide motif showed lower affinity for FGF-1. FGF-2 was shown to bind to a mono-O-sulfated HS 6-mer carrying a single internal IdoUA(2-OSO3)-unit. However, a di-O-sulfated -IdoUA(2-OSO3)-GlcNSO3-IdoUA(2-OSO3)-trisaccharide sequence within a HS 8-mer gave stronger binding. These findings show that not only the number but also the positions of individual sulfate groups determine affinity of HS for FGFs. Our findings support the notion that FGF-dependent processes can be modulatedin vivo by regulated expression of distinct HS sequences. heparan sulfate 2,5-anhydro-d-[1-3H]mannitol fibroblast growth factor fibroblast growth factor receptor d-glucuronic acid glucosamine-6-sulfatase N-sulfoglucosamine hexuronic acid l-iduronic acid α-l-iduronidase iduronate-2-sulfatase, MALDI-TOF, matrix assisted laser desorption ionization-time of flight partial cleavage with HNO2 N-sulfated Heparan sulfate (HS)1proteoglycans are present on the surface of all adherent mammalian cells as well as in the extracellular matrix. The biological functions of the structurally diverse HS chains are mediated through binding to a variety of proteins, including enzymes, enzyme inhibitors, cytokines/growth factors, and extracellular matrix molecules (1Bernfield M. Götte M. Park P.W. Reizes O. Fitzgerald M.L. Lincecum J. Zako M. Annu. Rev. Biochem. 1999; 68: 729-777Crossref PubMed Scopus (2295) Google Scholar, 2Salmivirta M. Lidholt K. Lindahl U. FASEB J. 1996; 10: 1270-1279Crossref PubMed Scopus (393) Google Scholar, 3Lindahl U. Kusche-Gullberg M. Kjellén L. J. Biol. Chem. 1998; 273: 24979-24982Abstract Full Text Full Text PDF PubMed Scopus (569) Google Scholar, 4Lyon M. Gallagher J.T. Matrix. Biol. 1998; 17: 485-493Crossref PubMed Scopus (113) Google Scholar). More than 100 proteins have been reported to interact with the HS moiety of HS proteoglycan or with heparin, a more highly sulfated related polysaccharide. The best studied example of such binding is that of antithrombin, which interacts with a specific pentasaccharide sequence that carries several sulfate groups in critical positions (5Bourin M.-C. Lindahl U. Biochem. J. 1993; 289: 313-330Crossref PubMed Scopus (392) Google Scholar). A question of current interest is whether other proteins also bind specifically to distinct saccharide epitopes. Although many proteins bind the highly sulfated heparin structure, it has been proposed that the same ligands may selectively interact with cognate HS species containing more sparsely distributed sulfate groups (2Salmivirta M. Lidholt K. Lindahl U. FASEB J. 1996; 10: 1270-1279Crossref PubMed Scopus (393) Google Scholar). Research of the last decade has indeed identified a multitude of physiologically and pathophysiologically important processes that depend on HS/protein interactions (1Bernfield M. Götte M. Park P.W. Reizes O. Fitzgerald M.L. Lincecum J. Zako M. Annu. Rev. Biochem. 1999; 68: 729-777Crossref PubMed Scopus (2295) Google Scholar, 5Bourin M.-C. Lindahl U. Biochem. J. 1993; 289: 313-330Crossref PubMed Scopus (392) Google Scholar, 6Esko, J. D., and Lindahl, U. (2001) J. Clin. Invest., in press.Google Scholar, 7Maccarana M. Sakura Y. Tawada A. Yoshida K. Lindahl U. J. Biol. Chem. 1996; 271: 17804-17810Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar).The structural diversity of HS is generated during biosynthesis of the polysaccharide (2Salmivirta M. Lidholt K. Lindahl U. FASEB J. 1996; 10: 1270-1279Crossref PubMed Scopus (393) Google Scholar, 3Lindahl U. Kusche-Gullberg M. Kjellén L. J. Biol. Chem. 1998; 273: 24979-24982Abstract Full Text Full Text PDF PubMed Scopus (569) Google Scholar, 6Esko, J. D., and Lindahl, U. (2001) J. Clin. Invest., in press.Google Scholar). A polymer of alternatingd-glucuronic acid (GlcUA) and GlcNAc units, joined in [GlcUAβ1,4GlcNAcα1,4]n structure, is modified through N-deacetylation/N-sulfation of GlcNAc units, C-5 epimerization of GlcUA tol-iduronic acid (IdoUA), and O-sulfation at various locations (C-2 of IdoUA and GlcUA and C-3 and C-6 of GlcN units). The modification reactions are generally incomplete, thus generating the diverse distribution ofN-substituents, GlcUA/IdoUA units, and sulfate groups typical for HS. Although the mechanisms in control of polymer modification are not fully understood, it is clear that the number of distinct saccharide epitopes actually expressed will be restricted because of the substrate specificities of the enzymes involved. Much of the structural variability within HS chains resides in the contiguousN-sulfated (NS) regions, which are interspersed by essentially unmodified N-acetylated sequences and by alternating N-acetylated and NS disaccharide units (7Maccarana M. Sakura Y. Tawada A. Yoshida K. Lindahl U. J. Biol. Chem. 1996; 271: 17804-17810Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar, 8Merry C.L. Lyon M. Deakin J.A. Hopwood J.J. Gallagher J.T. J. Biol. Chem. 1999; 274: 18455-18462Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 9Safaiyan F. Lindahl U. Salmivirta M. Biochemistry. 2000; 39: 10823-10830Crossref PubMed Scopus (36) Google Scholar). “Heparin,” in this context, may be considered an unusually extended and highly O-sulfated NS domain.Compositional analysis of HS preparations from different tissues (7Maccarana M. Sakura Y. Tawada A. Yoshida K. Lindahl U. J. Biol. Chem. 1996; 271: 17804-17810Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar,10Lindahl B. Eriksson L. Lindahl U. Biochem. J. 1995; 306: 177-184Crossref PubMed Scopus (98) Google Scholar, 11Lyon M. Deakin J.A. Gallagher J.T. J. Biol. Chem. 1994; 269: 11208-11215Abstract Full Text PDF PubMed Google Scholar) as well as immunohistochemical evidence (12van Kuppevelt T.H. Dennissen M.A. van Venrooij W.J. Hoet R.M. Veerkamp J.H. J. Biol. Chem. 1998; 273: 12960-12966Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar, 13van den Born J. Gunnarsson K. Bakker M.A.H. Kjellén L. Kusche-Gullberg M. Maccarana M. Berden J.H.M. Lindahl U. J. Biol. Chem. 1995; 270: 31303-31309Crossref PubMed Scopus (133) Google Scholar) point to differential regulation of HS biosynthesis, which may be modulated in normal development and aging (14Nurcombe V. Ford M.D. Wildschut J.A. Bartlett P.F. Science. 1993; 260: 103-106Crossref PubMed Scopus (370) Google Scholar, 15Feyzi E. Saldeen T. Larsson E. Lindahl U. Salmivirta M. J. Biol. Chem. 1998; 273: 13395-13398Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar) and perturbed in disease (16Lindahl B. Lindahl U. J. Biol. Chem. 1997; 272: 26091-26094Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). It is believed that subtle changes in HS structure may result in altered interaction with proteins, and such effects have recently been demonstrated (15Feyzi E. Saldeen T. Larsson E. Lindahl U. Salmivirta M. J. Biol. Chem. 1998; 273: 13395-13398Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar, 17Nurcombe V. Smart C.E. Chipperfield H. Cool S.M. Boilly B. Hondermarck H. J. Biol. Chem. 2000; 275: 30009-30018Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 18Kreuger J. Prydz K. Pettersson R.F. Lindahl U. Salmivirta M. Glycobiology. 1999; 9: 723-729Crossref PubMed Scopus (76) Google Scholar). Although we thus assume that many proteins recognize distinct HS epitopes, the minimal requirements, in terms of HS structure, for interaction with a given protein have still been defined only for antithrombin. Moreover, we note that whereas the antithrombin-binding sequence features a “rare” component, the 3-O-sulfated GlcN unit (5Bourin M.-C. Lindahl U. Biochem. J. 1993; 289: 313-330Crossref PubMed Scopus (392) Google Scholar), it seems likely that most other proteins interact with structures made up of the commonly occurring disaccharide units (19Casu, B., and Lindahl, U. (2001) Adv. Carbohydr. Chem. Biochem., in press.Google Scholar).More than 20 members of the FGF family have been identified, and most of these growth factors bind heparin/HS. Experiments with the prototype species, acidic FGF (FGF-1) and basic FGF (FGF-2), using target cells deficient in HS biosynthesis have shown that the growth factors depend on cell surface HS for their mitogenic activity (20Rapraeger A.C. Krufka A. Olwin B.B. Science. 1991; 252: 1705-1708Crossref PubMed Scopus (1285) Google Scholar, 21Yayon A. Klagsbrun M. Esko J.D. Leder P. Ornitz D.M. Cell. 1991; 64: 841-848Abstract Full Text PDF PubMed Scopus (2074) Google Scholar, 22Guimond S. Maccarana M. Olwin B.B. Lindahl U. Rapraeger A.C. J. Biol. Chem. 1993; 268: 23906-23914Abstract Full Text PDF PubMed Google Scholar, 23Ishihara M. Glycobiology. 1994; 4: 817-824Crossref PubMed Scopus (104) Google Scholar, 24Pye D.A. Vivès R.R. Turnbull J.E. Hyde P. Gallagher J.T. J. Biol. Chem. 1998; 273: 22936-22942Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar). The HS-deficient cells turn responsive to growth factor upon addition of exogenous heparin (that is normally contained in intracellular granules of the mast cell, thus unable to interact with extracellular growth factors). Experiments using selectively desulfated heparin preparations pointed to distinct O-sulfate requirements for interactions with FGF-1 (both IdoUA 2-O-sulfate and GlcN 6-O-sulfate groups) and FGF-2 (2-O-sulfate only) (22Guimond S. Maccarana M. Olwin B.B. Lindahl U. Rapraeger A.C. J. Biol. Chem. 1993; 268: 23906-23914Abstract Full Text PDF PubMed Google Scholar, 23Ishihara M. Glycobiology. 1994; 4: 817-824Crossref PubMed Scopus (104) Google Scholar, 25Maccarana M. Casu B. Lindahl U. J. Biol. Chem. 1993; 268: 23898-23905Abstract Full Text PDF PubMed Google Scholar, 26Ishihara M. Shaklee P.N. Yang Z. Liang W. Wei Z. Stack R.J. Holme K. Glycobiology. 1994; 4: 451-458Crossref PubMed Scopus (91) Google Scholar), in accord with results of compositional analysis of affinity-fractionated HS oligomers (18Kreuger J. Prydz K. Pettersson R.F. Lindahl U. Salmivirta M. Glycobiology. 1999; 9: 723-729Crossref PubMed Scopus (76) Google Scholar, 25Maccarana M. Casu B. Lindahl U. J. Biol. Chem. 1993; 268: 23898-23905Abstract Full Text PDF PubMed Google Scholar, 27Habuchi H. Suzuki S. Saito T. Tamura T. Harada T. Yoshida K. Kimata K. Biochem. J. 1992; 285: 805-813Crossref PubMed Scopus (163) Google Scholar, 28Turnbull J.E. Fernig D.G. Ke Y. Wilkinson M.C. Gallagher J.T. J. Biol. Chem. 1992; 267: 10337-10341Abstract Full Text PDF PubMed Google Scholar). Moreover, selected preparations of native HS were found to differ in their ability to promote FGF-1- and FGF-2-induced biological responses (17Nurcombe V. Smart C.E. Chipperfield H. Cool S.M. Boilly B. Hondermarck H. J. Biol. Chem. 2000; 275: 30009-30018Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar). However, most information so far available regarding the molecular aspects of FGF/polysaccharide interactions derives from crystallographic analysis of growth factors complexed with fully sulfated heparin oligosaccharides, with or without FGF receptor (FGFR) ectodomains (29Faham S. Hileman R.E. Fromm J.R. Linhardt R.J. Rees D.C. Science. 1996; 271: 1116-1120Crossref PubMed Scopus (732) Google Scholar, 30DiGabriele A.D. Lax I. Chen D.I. Svahn C.M. Jaye M. Schlessinger J. Hendrickson W.A. Nature. 1998; 393: 812-817Crossref PubMed Scopus (324) Google Scholar, 31Pellegrini L. Burke D.F. von Delft F. Mulloy B. Blundell T.L. Nature. 2000; 407: 1029-1034Crossref PubMed Scopus (621) Google Scholar, 32Schlessinger J. Plotnikov A.N. Ibrahimi O.A. Eliseenkova A.V. Yeh B.K. Yayon A. Linhardt R.J. Mohammadi M. Mol. Cell. 2000; 6: 743-750Abstract Full Text Full Text PDF PubMed Scopus (948) Google Scholar). Intriguingly, the patterns revealed by these studies were highly diverse with respect to orientation, contact sites, and even stoichiometry of the interacting species. Nevertheless, binding of FGF to saccharide sequences spanning six monosaccharide units or less was a common feature of all models, presumably essential to receptor activation and intracellular signaling. The HS proteoglycan thus is ascribed a co-receptor function in which the HS chain interacts with the growth factor and, in most models postulated, also with the FGF tyrosine kinase receptor. The HS domain required to span growth factor and receptor extends beyond the sequence committed to growth factor binding alone (22Guimond S. Maccarana M. Olwin B.B. Lindahl U. Rapraeger A.C. J. Biol. Chem. 1993; 268: 23906-23914Abstract Full Text PDF PubMed Google Scholar, 31Pellegrini L. Burke D.F. von Delft F. Mulloy B. Blundell T.L. Nature. 2000; 407: 1029-1034Crossref PubMed Scopus (621) Google Scholar, 32Schlessinger J. Plotnikov A.N. Ibrahimi O.A. Eliseenkova A.V. Yeh B.K. Yayon A. Linhardt R.J. Mohammadi M. Mol. Cell. 2000; 6: 743-750Abstract Full Text Full Text PDF PubMed Scopus (948) Google Scholar). A recent study from our laboratory identifies HS sequences interacting with one of the FGFR species (33Loo B.-M. Kreuger J. Jalkanen M. Lindahl U. Salmivirta M. J. Biol. Chem. 2001; 276: 16868-16876Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar).Contrary to heparin oligosaccharides, abundantly available, an oligosaccharide derived from authentic HS and selected for ability to interact with a given protein will usually be obtained in minute, often subnanomol, quantities. The methods for sequence analysis of such samples have only recently been developed (34Turnbull J.E. Hopwood J.J. Gallagher J.T. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 2698-2703Crossref PubMed Scopus (139) Google Scholar, 35Venkataraman G. Shriver Z. Raman R. Sasisekharan R. Science. 1999; 286: 537-542Crossref PubMed Scopus (217) Google Scholar, 36Vives R.R. Pye D.A. Salmivirta M. Hopwood J.J. Lindahl U. Gallagher J.T. Biochem. J. 1999; 339: 767-773Crossref PubMed Scopus (86) Google Scholar). In the present study, we have applied one of these procedures to a series of HS oligosaccharides isolated from pig mucosal HS and fractionated with regard to affinity for FGF-1. A minimal “binding motif” is identified, with three O-sulfate groups in fixed positions, although additional O-sulfation may increase the affinity depending on position. Using similar experimental protocol and scope we also reassess the interaction between HS and FGF-2.DISCUSSIONCompelling evidence from many research groups implicate HS proteoglycans with a “co-receptor” function in FGF signaling (see the Introduction). The precise role of the HS chain is still somewhat unclear, because it appears to interact not only with the growth factor but also with the receptor protein. Nevertheless, recent findings suggest that subtle modulation of HS structure may alter cellular responsiveness to FGFs (17Nurcombe V. Smart C.E. Chipperfield H. Cool S.M. Boilly B. Hondermarck H. J. Biol. Chem. 2000; 275: 30009-30018Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 24Pye D.A. Vivès R.R. Turnbull J.E. Hyde P. Gallagher J.T. J. Biol. Chem. 1998; 273: 22936-22942Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar, 39Rahmoune H. Chen H.L. Gallagher J.T. Rudland P.S. Fernig D.G. J. Biol. Chem. 1998; 273: 7303-7310Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar). Analysis of such modulation has so far been hampered by lack of methodology, in particular the inability to determine the fine structure, i.e. sequence of sulfated HS domains involved in protein binding. A recently developed method for sequence analysis has been applied to the characterization of HS domains interacting with FGF-1 and FGF-2. These applications show that heparin/HS-derived oligosaccharides in the low pmol range are amenable to sequence analysis. The novel sequencing technology, including the recent mass spectrometry-based approaches (35Venkataraman G. Shriver Z. Raman R. Sasisekharan R. Science. 1999; 286: 537-542Crossref PubMed Scopus (217) Google Scholar), will greatly reinforce studies of the structure/function relations of HS.The structural requirements for interaction of HS with FGF-2 are relatively simple, a single IdoUA 2-O-sulfate group appropriately located in an NS domain being sufficient for appreciable affinity and an additional 2-O-sulfate group being sufficient for strong binding (Fig.10 C). Accordingly, most of the octamers tested, even from the low sulfated aortic HS, bound the FGF-2 column (Fig. 8). The ability to bind FGF-2 thus would seem to be constitutively expressed by most HS species. By contrast, the more complex sequences required for high affinity (≥0.5 m NaCl) interaction with FGF-1 occur in only ∼5% of all isolatedN-sulfated octamers from (the more highly sulfated) intestinal mucosa HS (Fig. 2). Such binding was found to require a characteristic tri-O-sulfated trisaccharide motif, minimally expressed in octasaccharide 8f, that could not be substituted for by other structures containing a larger number of sulfate groups within the same octamer framework (Fig. 10 A) (the relative importance of individual N-sulfate groups is not assessed in the present study). The subtle specificity of the interaction is illustrated by comparison of structures 8b(low affinity, 0.2 m NaCl) and 8f (high affinity, 0.5 m NaCl), which differ by the location of a single 6-O-sulfate group. Binding strength could be further increased by additional 6-O-sulfation, but only given the presence of the basic binding trisaccharide motif. By contrast, this motif contributed less to FGFR-4 binding than a larger number of more sparsely distributed O-sulfate groups (Fig. 10 B) (33Loo B.-M. Kreuger J. Jalkanen M. Lindahl U. Salmivirta M. J. Biol. Chem. 2001; 276: 16868-16876Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). These findings point to the importance of regulation in HS biosynthesis, particularly regarding the distribution of 6-O-sulfate groups and add to the significance of recent studies of biosynthetic 6-O-sulfation patterning in HS domains (8Merry C.L. Lyon M. Deakin J.A. Hopwood J.J. Gallagher J.T. J. Biol. Chem. 1999; 274: 18455-18462Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 9Safaiyan F. Lindahl U. Salmivirta M. Biochemistry. 2000; 39: 10823-10830Crossref PubMed Scopus (36) Google Scholar).Our results relating oligosaccharide structure to affinity for, in particular, FGF-1 suggest that HS sequences may be tailored to bind protein ligands with graded strength. At present we can only speculate over the functional meaning of such an arrangement. It should be emphasized that the HS chains serving as starting material for the preparation of labeled oligosaccharides were derived from complex tissues (intestinal mucosa and vascular wall), presumably from a variety of proteoglycan species variously located at cell surfaces and in the extracellular matrix. We have no information regarding the distribution of differentially sulfated NS domains between these proteoglycans, nor do we know whether all of these domains, only selected subpopulations, or yet other domains with mixed acetyl and sulfate N-substituents (not evaluated in the present study) are accessible to functional interactions with different FGFs in the intact tissues. Moreover, the HS/FGF-1 interaction may fulfill various biological purposes. Importantly, modulation of the binding of FGF to HS may regulate FGF-FGFR complex formation, receptor dimerization, and activation. However, the interaction may also serve to protect FGF against proteolysis (40Yoneda A. Asada M. Oda Y. Suzuki M. Imamura T. Nat. Biotech. 2000; 18: 641-644Crossref PubMed Scopus (32) Google Scholar), control growth factor distribution in tissues (41Chang Z. Meyer K. Rapraeger A.C. Friedl A. FASEB J. 2000; 14: 137-144Crossref PubMed Scopus (94) Google Scholar), and capture growth factors for HS-mediated “facilitated diffusion” toward molecular encounters at the cell surface (42Lander A.D. Matrix Biol. 1998; 17: 465-472Crossref PubMed Scopus (103) Google Scholar).The first attempt at defining the minimal structural requirements for HS interacting with FGF-2 (25Maccarana M. Casu B. Lindahl U. J. Biol. Chem. 1993; 268: 23898-23905Abstract Full Text PDF PubMed Google Scholar) implicated a pentasaccharide sequence with three hexuronic acid units and two N-sulfated GlcN residues, the reducing-terminal IdoUA unit being 2-O-sulfated (Fig. 10 C). Lacking methods at the time for direct sequencing, the binding structure was deduced from the compositional analysis of oligosaccharides from different sources, including partially O-desulfated heparin. This structure was recovered within one of the FGF-2-binding HS octamers (8l) identified in the present work. The IdoUA 2-O-sulfate group on unit 5 was found also in octasaccharide 8m, which bound FGF-2 with higher affinity. The increase in affinity was likely due to the additional 2-O-sulfate residue on unit 3. These structures may be compared with the binding motif deduced from crystallographic analysis, by Faham et al. (29Faham S. Hileman R.E. Fromm J.R. Linhardt R.J. Rees D.C. Science. 1996; 271: 1116-1120Crossref PubMed Scopus (732) Google Scholar) of a complex between FGF-2 and a fully sulfated heparin hexasaccharide. This motif included the 2-O-sulfate group on unit 3 but not the one on unit 5. Yet another FGF-2-binding motif was put forth by Schlessingeret al. (32Schlessinger J. Plotnikov A.N. Ibrahimi O.A. Eliseenkova A.V. Yeh B.K. Yayon A. Linhardt R.J. Mohammadi M. Mol. Cell. 2000; 6: 743-750Abstract Full Text Full Text PDF PubMed Scopus (948) Google Scholar) in their study of a FGF-2/FGFR-1/heparin 10-mer complex (Fig. 10 C). Notably, although this motif again differed from that deduced by Faham et al. (29Faham S. Hileman R.E. Fromm J.R. Linhardt R.J. Rees D.C. Science. 1996; 271: 1116-1120Crossref PubMed Scopus (732) Google Scholar), both structures are covered by HS octasaccharide8m. 7According to Schlessinger et al. (32Schlessinger J. Plotnikov A.N. Ibrahimi O.A. Eliseenkova A.V. Yeh B.K. Yayon A. Linhardt R.J. Mohammadi M. Mol. Cell. 2000; 6: 743-750Abstract Full Text Full Text PDF PubMed Scopus (948) Google Scholar) 6-O-sulfate groups on units 2 and 6 contribute weakly to the interaction. Also, variable sets of sulfate groups in a heparin 10-mer could contribute to FGF-1 binding, as shown by DiGabriele et al. (30DiGabriele A.D. Lax I. Chen D.I. Svahn C.M. Jaye M. Schlessinger J. Hendrickson W.A. Nature. 1998; 393: 812-817Crossref PubMed Scopus (324) Google Scholar). These observations suggest that the interaction potential of HS sequences may not be readily deduced from crystal data involving heparin (used as a substitute for the authentic HS provided at the cell surface). Similar concern potentially applies also to the recent crystallographic analyses of more complex interaction systems, involving growth factors, extracellular receptor domains, and heparin oligomers (31Pellegrini L. Burke D.F. von Delft F. Mulloy B. Blundell T.L. Nature. 2000; 407: 1029-1034Crossref PubMed Scopus (621) Google Scholar, 32Schlessinger J. Plotnikov A.N. Ibrahimi O.A. Eliseenkova A.V. Yeh B.K. Yayon A. Linhardt R.J. Mohammadi M. Mol. Cell. 2000; 6: 743-750Abstract Full Text Full Text PDF PubMed Scopus (948) Google Scholar). We anticipate that interaction studies, by crystallography as well as other methods, will be refined through the future availability of synthetic homogeneous oligosaccharides that express the minimal structural features required for interactions with growth factors and receptors. Heparan sulfate (HS)1proteoglycans are present on the surface of all adherent mammalian cells as well as in the extracellular matrix. The biological functions of the structurally diverse HS chains are mediated through binding to a variety of proteins, including enzymes, enzyme inhibitors, cytokines/growth factors, and extracellular matrix molecules (1Bernfield M. Götte M. Park P.W. Reizes O. Fitzgerald M.L. Lincecum J. Zako M. Annu. Rev. Biochem. 1999; 68: 729-777Crossref PubMed Scopus (2295) Google Scholar, 2Salmivirta M. Lidholt K. Lindahl U. FASEB J. 1996; 10: 1270-1279Crossref PubMed Scopus (393) Google Scholar, 3Lindahl U. Kusche-Gullberg M. Kjellén L. J. Biol. Chem. 1998; 273: 24979-24982Abstract Full Text Full Text PDF PubMed Scopus (569) Google Scholar, 4Lyon M. Gallagher J.T. Matrix. Biol. 1998; 17: 485-493Crossref PubMed Scopus (113) Google Scholar). More than 100 proteins have been reported to interact with the HS moiety of HS proteoglycan or with heparin, a more highly sulfated related polysaccharide. The best studied example of such binding is that of antithrombin, which interacts with a specific pentasaccharide sequence that carries several sulfate groups in critical positions (5Bourin M.-C. Lindahl U. Biochem. J. 1993; 289: 313-330Crossref PubMed Scopus (392) Google Scholar). A question of current interest is whether other proteins also bind specifically to distinct saccharide epitopes. Although many proteins bind the highly sulfated heparin structure, it has been proposed that the same ligands may selectively interact with cognate HS species containing more sparsely distributed sulfate groups (2Salmivirta M. Lidholt K. Lindahl U. FASEB J. 1996; 10: 1270-1279Crossref PubMed Scopus (393) Google Scholar). Research of the last decade has indeed identified a multitude of physiologically and pathophysiologically important processes that depend on HS/protein interactions (1Bernfield M. Götte M. Park P.W. Reizes O. Fitzgerald M.L. Lincecum J. Zako M. Annu. Rev. Biochem. 1999; 68: 729-777Crossref PubMed Scopus (2295) Google Scholar, 5Bourin M.-C. Lindahl U. Biochem. J. 1993; 289: 313-330Crossref PubMed Scopus (392) Google Scholar, 6Esko, J. D., and Lindahl, U. (2001) J. Clin. Invest., in press.Google Scholar, 7Maccarana M. Sakura Y. Tawada A. Yoshida K. Lindahl U. J. Biol. Chem. 1996; 271: 17804-17810Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar). The structural diversity of HS is generated during biosynthesis of the polysaccharide (2Salmivirta M. Lidholt K. Lindahl U. FASEB J. 1996; 10: 1270-1279Crossref PubMed Scopus (393) Google Scholar, 3Lindahl U. Kusche-Gullberg M. Kjellén L. J. Biol. Chem. 1998; 273: 24979-24982Abstract Full Text Full Text PDF PubMed Scopus (569) Google Scholar, 6Esko, J. D., and Lindahl, U. (2001) J. Clin. Invest., in press.Google Scholar). A polymer of alternatingd-glucuronic acid (GlcUA) and GlcNAc units, joined in [GlcUAβ1,4GlcNAcα1,4]n structure, is modified through N-deacetylation/N-sulfation of GlcNAc units, C-5 epimerization of GlcUA tol-iduronic acid (IdoUA), and O-sulfation at various locations (C-2 of IdoUA and GlcUA and C-3 and C-6 of GlcN units). The modification reactions are generally incomplete, thus generating the diverse distribution ofN-substituents, GlcUA/IdoUA units, and sulfate groups typical for HS. Although the mechanisms in control of polymer modification are not fully understood, it is clear that the number of distinct saccharide epitopes actually expressed will be restricted because of the substrate specificities of the enzymes involved. Much of the structural variability within HS chains resides in the contiguousN-sulfated (NS) regions, which are interspersed by essentially unmodified N-acetylated sequences and by alternating N-acetylated and NS disaccharide units (7Maccarana M. Sakura Y. Tawada A. Yoshida K. Lindahl U. J. Biol. Chem. 1996; 271: 17804-17810Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar, 8Merry C.L. Lyon M. Deakin J.A. Hopwood J.J. Gallagher J.T. J. Biol. Chem. 1999; 274: 18455-18462Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 9Safaiyan F. Lindahl U. Salmivirta M. Biochemistry. 2000; 39: 10823-10830Crossref PubMed Scop" @default.
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