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Heparin, Heparan Sulphate and the TGF-Β Cytokine Superfamily

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Heparin, Heparan Sulphate and the TGF-Β Cytokine Superfamily molecules Review Heparin, Heparan Sulphate and the TGF-β Cytokine Superfamily Chris C. Rider * and Barbara Mulloy Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, Surrey TW20 0EX, UK; [email protected] * Correspondence: [email protected] Academic Editors: Giangiacomo Torri and Jawed Fareed Received: 29 March 2017; Accepted: 26 April 2017; Published: 29 April 2017 Abstract: Of the circa 40 cytokines of the TGF-β superfamily, around a third are currently known to bind to heparin and heparan sulphate. This includes TGF-β1, TGF-β2, certain bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), as well as GDNF and two of its close homologues. Experimental studies of their heparin/HS binding sites reveal a diversity of locations around the shared cystine-knot protein fold. The activities of the TGF-β cytokines in controlling proliferation, differentiation and survival in a range of cell types are in part regulated by a number of specific, secreted BMP antagonist proteins. These vary in structure but seven belong to the CAN or DAN family, which shares the TGF-β type cystine-knot domain. Other antagonists are more distant members of the TGF-β superfamily. It is emerging that the majority, but not all, of the antagonists are also heparin binding proteins. Any future exploitation of the TGF-β cytokines in the therapy of chronic diseases will need to fully consider their interactions with glycosaminoglycans and the implications of this in terms of their bioavailability and biological activity. Keywords: heparin; heparan sulphate; TGF-β; bone morphogenetic protein (BMP); growth and differentiation factor (GDF); GDNF; BMP antagonists; noggin; sclerostin; gremlin 1. The TGF-β Cytokine Superfamily The vertebrate TGF-β superfamily comprises some 40 cytokines, which regulate cellular activities encompassing proliferation, differentiation, and survival in diverse cell types (for reviews see [1–3]). They are thus important in tissue morphogenesis and development, as well as in regulating tissue homeostasis in the adult. Accordingly some members of the superfamily have come to the fore in the field of regenerative medicine, such as in the maintenance and subsequent differentiation of embryonic stem cells [1]. Moreover, aberrant signalling by TGF-β family cytokines occurs in a range of chronic diseases including tissue fibrosis and various cancers, and thus an understanding of their roles and modes of action is of relevance in effort to develop effective therapies for such diseases. Within the superfamily, there are three TGF-βs [2], four activins [3], four neurotropic factors [4] and 21 bone morphogenetic proteins (BMPs)/growth and differentiation factors (GDFs) [5]. Across the superfamily a number of different receptors and signalling pathways are employed, but the canonical signalling pathway is via a complex of Type I and Type II serine/threonine kinases, cell surface receptors which activate cytoplasmic Smad transcription factors. The field of TGF-β family cytokine signalling and receptor usage has recently been reviewed elsewhere [6]. A further superfamily feature is a commonality of structure based on a cystine knot motif (Figure1) Although variations occur, this typically contains within a sequence of some 110 residues, seven cysteines, of which six form intrachain disulphide bridges with the connectivity of CyS1-CyS5, CyS2-Cys6, and Cys3-CyS7. These covalent bridges give rise to a true knot structure, as CyS -2, -3, -6 and -7 together with neighbouring amino acids in the polypeptide chain, form an eight-membered Molecules 2017, 22, 713; doi:10.3390/molecules22050713 www.mdpi.com/journal/molecules Molecules 2017, 22, 713 2 of 11 Molecules 2017, 22, 713 2 of 11 circle of covalently linked residues, through which the CyS1-CyS5 linkage passes [7]. This covalent of covalently linked residues, through which the CyS1-CyS5 linkage passes [7]. This covalent knot knot holds together a polypeptide fold in which two narrow β-strand finger loops project in near holds together a polypeptide fold in which two narrow β-strand finger loops project in near parallel parallel from one face of a short α-helix [8,9]. A simply analogy of this structure is that of a hand from one face of a short α-helix [8,9]. A simply analogy of this structure is that of a hand (Figure 1A) β (Figurebearing1A) only bearing two slightly only two curved slightly fingers curved (the fingersβ-strand (the loops).-strand The cystine loops). knot The region cystine provides knot region the α providespalm, with the palm,the α-helix with comprising the -helix the comprising heel or wrist the heelof the or hand. wrist Many of the but hand. not Manyall of the but superfamily not all of the superfamilymembers exist members as covalently exist as linked covalently dimers, linked held together dimers, by held an interchain together bydisulphide an interchain bridge disulphidebetween bridgethe two between Cys4 residues the two which Cys4residues are un-partnered which are within un-partnered the monomeric within structure. the monomeric This covalent structure. bridge This covalentgives rise bridge to an gives elongated, rise to offset, an elongated, face-to-face offset, dimer face-to-face in which dimer the paired in which β-strand the pairedfinger loopsβ-strand of each finger loopssubunit of each extend subunit away extend from the away each from other the at eachopposite other ends at oppositeof the structure ends of (Figure the structure 1B). (Figure1B). FigureFigure 1. 1.The TheTGF- TGF-ββ superfamilysuperfamily cystinecystine knot fold, fold, as as typified typified by by TGF- TGF-β1β 1(co-ordinates (co-ordinates from from 1KLC.pdb).1KLC.pdb). Protein Protein chains chains are are shown shown inin ribbonribbon format: ββ-strands-strands are are blue, blue, helices helices red, red, turns turns green; green; cystinescystines are are shown shown in in yellow yellow stick stick format. format. ((AA)) TGF-TGF-β11 monomer monomer showing showing the the “hand” “hand” structures, structures, with with thethe cystine cystine knot knot indicated indicated by by a a green green ellipse. ellipse. ((BB)) TGF-β11 dimer, dimer, the the “wrist” “wrist” of of each each hand hand is iscupped cupped in in the other subunit. The view of the dimer is rotated by 90° with respect to the plane of 1A. The the other subunit. The view of the dimer is rotated by 90◦ with respect to the plane of 1A. The interchain interchain disulphide bridge is visible in the centre of the structure. disulphide bridge is visible in the centre of the structure. 2. Protein Antagonists of TGF-β Cytokines 2. Protein Antagonists of TGF-β Cytokines The activities of a number of the TGF-β superfamily members are tightly regulated, in part throughThe activities several secreted of a number antagonist of the proteins TGF- βwhichsuperfamily bind certain members of these arecytoki tightlynes with regulated, high affinity, in part throughinhibiting several cell secretedsurface antagonistreceptor engagement, proteins which and bindthereby certain signalling. of these These cytokines antagonists with high include affinity, inhibitingNoggin, cellTwisted surface Gastrulation receptor (TSG), engagement, Chordin andand Chordin-like thereby signalling. proteins, Theseand Follistatin antagonists (FST) include and Noggin,Follistatin Twisted like proteins Gastrulation (FSTLs). (TSG), These Chordin antagonist and proteins Chordin-like were proteins,initially recognised and Follistatin through (FST) their and Follistatinimportant like roles proteins in embryonic (FSTLs). development These antagonist [10]. A furt proteinsher family were of initiallyseven anta recognisedgonists is the through Cerberus their importantor Dan (CAN) roles family, in embryonic which comprises development Cerberus, [10]. Coco, A further Dan, Gremlin family (also of seven referred antagonists to as Gremlin- is the Cerberus1), PRDC/gremlin-2, or Dan (CAN) Sclerostin family, and which USAG-1. comprises Remarkably, Cerberus, the CAN Coco, family Dan, antagonists Gremlin (also are also referred TGF- to asβ Gremlin-1), superfamily PRDC/gremlin-2, members, by virtue Sclerostin of possessing and USAG-1. the characteristic Remarkably, eight-membered the CAN family cystine-knot antagonists aredomain also TGF- [7]. βThesuperfamily non-CAN antagonists, members, TSG, by virtue Chordi ofn, possessing and Noggin, the but characteristic not Follistatin, eight-membered possess more cystine-knotdiverse variants domain of [the7]. cystine-knot The non-CAN motif antagonists, within their TSG, larger Chordin, structures, and Noggin,and therefore but not are Follistatin, distant possessmembers more of diverse the TGF- variantsβ superfamily of the cystine-knot [11]. motif within their larger structures, and therefore are distant members of the TGF-β superfamily [11]. 3. Interactions of TGF-β Cytokines with Heparin and Heparan Sulphate 3. InteractionsIt has emerged of TGF- βthatCytokines a number with of Heparinthe TGF-β and superfamily Heparan Sulphatecytokines bind to the sulphated polysaccharideIt has emerged heparin that and a numberheparan su oflphate the TGF- (HS)β withsuperfamily interactions cytokines strong enough bind to to be the relevant sulphated at polysaccharidephysiological ionic heparin strength and heparanand pH. This sulphate was first (HS) established with interactions in the case strong of TGF- enoughβ1 by McCaffrey to be relevant et al. [12]. Subsequently Lyon et al. [13] showed that heparin
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