Mohammadi M, Olsen SK, Goetz RA protein canyon in the FGF-FGF receptor dimer selects from an a la carte menu of heparan sulfate motifs. Curr Opin Struct Biol 15:506-516

Department of Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
Current Opinion in Structural Biology (Impact Factor: 7.2). 11/2005; 15(5):506-16. DOI: 10.1016/
Source: PubMed


Heparan sulfate (HS) is an essential and dynamic regulator of fibroblast growth factor (FGF) signaling. Two fundamentally different crystallographic models have been proposed to explain, at the molecular level, how HS/heparin enables FGF and FGF receptor (FGFR) to assemble into a functional dimer on the cell surface. In the symmetric 'two-end' model, the heparin-binding sites of FGF and FGFR merge to form a basic canyon that recruits two HS for binding. Within this canyon, the HS molecules primarily act to orchestrate and fortify multivalent and cooperative protein-protein contacts within the dimer that are the foundations of dimerization. In contrast, in the asymmetric model, which mechanistically resembles the previously proposed trans FGF dimer model, a single heparin molecule facilitates dimerization by cross-linking two FGFs into a trans dimer that brings together the two FGFRs. Interestingly, the crystal structure upon which the asymmetric model is based contains a symmetric dimer reminiscent of the symmetric two-end model, suggesting that a different interpretation of the crystal structure has led to the postulation of the asymmetric model. Importantly, the symmetric two-end model provides an intriguing solution to the problem of how HS selectivity is achieved in FGF signaling. The model reveals that, within the canyon, FGF and FGFR no longer adhere to their individual HS binding specificities, but instead act in unison to search for a unique HS motif from a plethora of HS epitopes that are expressed in a tissue-specific and developmentally regulated fashion. Primary sequence differences within the heparin-binding sites of FGFs and FGFRs, together with ligand-induced changes in FGFR conformation, lead to the formation of distinct canyons with unique HS specificity for individual FGF-FGFR complexes.

Download full-text


Available from: Regina Goetz
  • Source
    • "A generally held view is that ECM acts as a sink or reservoir for GFs and may assist in establishing stable gradients of GFs bound to ECM. In addition, GFs bound to ECM (as a solidphase ligand) can generate different signals compared with their soluble form (Mohammadi et al., 2005). Proteolytic processing of ECM can release matrix-sequestered GFs during injury or inflammation (Arroyo and Iruela-Arispe, 2010) inducing rapid and localized changes in the activity of these GFs. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Intensive research has demonstrated that extracellular matrix (ECM) molecules and growth factors (GF) collaborate at many different levels. The ability of ECM to modulate GF signals has important implications in tissue formation and homeostasis as well as novel therapies for acute and chronic wounds. Recently, a number of GF-binding sites was identified in fibronectin (FN) and was shown to provide another layer of regulation on GF signaling. Here, we review these new findings on FN interaction with GF in the context of general ways ECM molecules regulate GF signaling.Journal of Investigative Dermatology advance online publication, 12 December 2013; doi:10.1038/jid.2013.484.
    Full-text · Article · Dec 2013 · Journal of Investigative Dermatology
  • Source
    • "Of similar structure to ECM-derived heparan sulfate proteoglycans, heparin is also used in many delivery systems [35]. In addition to protecting growth factors from proteolytic degradation, heparin potentiates the activity of some factors by facilitating their interaction with cell receptors [36] [37]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Wound healing is a dynamic process that relies on coordinated signaling molecules to succeed. Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) is proven to accelerate healing, however precise control over its application is necessary to reduce side effects and achieve desired therapeutic benefit. To achieve effective growth factor delivery we designed a bioactive heparin-based coacervate. In vitro, HB-EGF released from the coacervate delivery system displayed enhanced bioactivity and promoted human keratinocyte migration while preserving cell proliferative capability. In a mouse excisional full-thickness wound model, controlled release of HB-EGF within the wound significantly accelerated wound closure more effectively than an equal dosage of free HB-EGF. Healing was induced by rapid re-epithelialization, granulation tissue formation, and accompanied by angiogenesis. Consistent with in vitro results, wounds treated with HB-EGF coacervate exhibited enhanced migration of keratinocytes with retained proliferative potential, forming a confluent layer for regained barrier function within 7days. Collectively, these results suggest that coacervate-based controlled release of HB-EGF may serve as a new therapy to accelerate healing of cutaneous wounds.
    Full-text · Article · Nov 2012 · Journal of Controlled Release
  • Source
    • "From this brief description of the general importance of GAG–protein binding and the HSPGs–chemokine interaction , in particular, it seems that HSPGs should be very interesting therapeutic targets for the development of anti-inflammatory strategies, especially in the context of chronic inflammation, autoimmune diseases and oncology/ angiogenesis (Rek et al., 2009b). In general, protein–GAG interactions are considered as molecular encounters with low affinity and low specificity, that is, (i) their dissociation constants (KD values) are found in the low micromolar range, although higher affinities (KD in the nanomolar range) especially for growth factors have been observed (Mohammadi et al., 2005), and (ii) their target glycan sequence is either not known at all (as for most chemokines) or can be estimated only from screening with animal-derived oligosaccharides. Contradicting this general observation, the high-affinity interaction of anti-thrombin III with its specific heparin pentasaccharide seems to be an exception to this rule. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Glycosaminoglycans (GAGs) are a class of highly negatively charged, unbranched, O-linked polysaccharides that are involved in many diseases. Their role as a protein-binding matrix on cell surfaces has long been recognized, but therapeutic approaches to interfere with protein-GAG interactions have been limited due to the complex chemistry of GAGs, on one hand, and due to the lack of specific antibodies against GAGs, on the other hand. We have developed a protein engineering platform (the so-called CellJammer(®) technology), which enables us to introduce higher GAG-binding affinity into wild-type GAG-binding proteins and to combine this with impaired biological, receptor-binding function. Chemokines are among the prototypic GAG-binding proteins and here we present selected results of our CellJammer technology applied to several of these proinflammatory proteins. An overview is given of our lead decoy protein, PA401, which is a CXCL8-based mutant protein with increased GAG-binding affinity and decreased CXCR1/2 binding and activation. Major results from our CCL2 and CCL5 programmes are also summarized and the potential for clinical application of these decoy proteins is presented.
    Full-text · Article · Jul 2012 · British Journal of Pharmacology
Show more