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Demystifying Heparan Sulfate–Protein Interactions UC San Diego UC San Diego Previously Published Works Title Demystifying heparan sulfate-protein interactions. Permalink https://escholarship.org/uc/item/0wj6876w Journal Annual review of biochemistry, 83(1) ISSN 0066-4154 Authors Xu, Ding Esko, Jeffrey D Publication Date 2014 DOI 10.1146/annurev-biochem-060713-035314 Peer reviewed eScholarship.org Powered by the California Digital Library University of California BI83CH06-Esko ARI 3 May 2014 10:35 Demystifying Heparan Sulfate–Protein Interactions Ding Xu and Jeffrey D. Esko Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California 92093; email: dxu@ucsd.edu, jesko@ucsd.edu Annu. Rev. Biochem. 2014. 83:129–57 Keywords First published online as a Review in Advance on heparin-binding protein, glycosaminoglycan, proteoglycan, March 6, 2014 glycan–protein interaction, heparan sulfate–binding domain, The Annual Review of Biochemistry is online at oligomerization biochem.annualreviews.org Annu. Rev. Biochem. 2014.83:129-157. Downloaded from www.annualreviews.org This article’s doi: Abstract 10.1146/annurev-biochem-060713-035314 Access provided by University of California - San Diego on 06/23/20. For personal use only. Numerous proteins, including cytokines and chemokines, enzymes and Copyright c 2014 by Annual Reviews. enzyme inhibitors, extracellular matrix proteins, and membrane recep- All rights reserved tors, bind heparin. Although they are traditionally classified as heparin- binding proteins, under normal physiological conditions these proteins actually interact with the heparan sulfate chains of one or more mem- brane or extracellular proteoglycans. Thus, they are more appropriately classified as heparan sulfate–binding proteins (HSBPs). This review pro- vides an overview of the various modes of interaction between heparan sulfate and HSBPs, emphasizing biochemical and structural insights that improve our understanding of the many biological functions of heparan sulfate. 129 BI83CH06-Esko ARI 3 May 2014 10:35 hundreds of proteins have evolved the capacity Contents to interact with HS, often with great specificity. This network of HS-binding proteins (HSBPs), INTRODUCTION.................. 130 termed the heparan sulfate interactome (4), DEFINITION OF A HEPARAN includes proteins involved in cell attachment, SULFATE–BINDING migration, invasion and differentiation, mor- PROTEIN........................ 132 phogenesis, organogenesis, blood coagulation, Heparan Sulfate–Binding Proteins lipid metabolism, inflammation, and responses Are Structurally Unrelated but to injury (5). All of these processes involve Evolutionarily Conserved . 133 physical docking of relevant HSBPs to car- Main Categories of Heparan bohydrate sequences within the HS chains. Sulfate–Binding Proteins . 133 The absence of HS is not compatible with life Heparan Sulfate–Binding Proteins (6, 7), a finding that reflects the capacity of May Bind Other HS to bind and modulate the activity of the Glycosaminoglycans . 133 HSBPs. MODES OF HEPARAN Like other macromolecules, HS can be SULFATE–PROTEIN divided into subunits, which are operationally INTERACTIONS................ 134 defined as disaccharides on the basis of the Basic Principles .................... 134 ability of bacterial enzymes or nitrous acid to Heparan Sulfate Can Act as a cleave the chain into its component units. The Tether......................... 134 basic building block consists of β1–4-linked Heparan Sulfate–Induced D-glucuronic acid (GlcA) and α1–4-linked Oligomerization . 135 N-acetyl-D-glucosamine (GlcNAc) (Figure 1). Heparan Sulfate as a Scaffold for The copolymer assembles while covalently Protein–Protein Interactions . 138 attached to a limited number of proteins, Heparan Sulfate as an Allosteric which are referred to as proteoglycan core Regulator. 139 proteins. Only 17 proteoglycans are known to SPECIFICITY OF HEPARAN contain HS (see the sidebar), although other SULFATE–PROTEIN proteoglycans are undoubtedly expressed in INTERACTIONS................ 142 a tissue-specific or developmentally regulated SpecificorNonspecific?............ 142 manner or in other organisms. During the Structural Features of Heparan assembly process, the chains undergo a series Sulfate–Binding Sites . 146 of processing reactions in which subsets OPPORTUNITIES AND of N-acetylglucosamine residues become CHALLENGES. 149 N-deacetylated and N-sulfated; adjacent glu- Annu. Rev. Biochem. 2014.83:129-157. Downloaded from www.annualreviews.org curonic acids undergo epimerization at C5 to Access provided by University of California - San Diego on 06/23/20. For personal use only. L-iduronic acid (IdoA); and ester-linked sulfate groups are installed at C2 of the uronic acids, at C6 of the glucosamine residues, and more INTRODUCTION rarely at C3 of the glucosamine residues. These Heparan sulfate (HS) is a linear sulfated gly- modification reactions do not go to completion, HS: heparan sulfate cosaminoglycan (GAG) expressed by virtually giving rise to sections of the chains with vari- GAG: all animal cells. It is an ancient molecule that ably sulfated domains (so-called NS domains), glycosaminoglycan is present in Cnidaria (e.g., Hydra) and all which are interspersed by NAc domains lacking HSBP: HS-binding metazoans analyzed to date, with the excep- all or most of these modifications, and mixed protein tion of Porifera (1–3). Amazingly, it has un- NAc/NS domains, which are located in the dergone very limited structural variation over transition zone between NS and NAc domains ∼500 million years of evolution. In contrast, (8, 9). Although all animal cells make HS, the 130 Xu · Esko BI83CH06-Esko ARI 3 May 2014 10:35 a OSO3- OSO3-6 OSO3- OSO3- OSO3- 5 O O O O O O O O O O - - - - - COO O OH COO O OH COO O OH COO O OH COO O OH O OH O OH O OH O OH O OH O 223 OSO3- NHSO3- OSO3- NHSO3- OSO3- NHSO3- OSO3- NHSO3- OSO3- NHSO3- IdoA2S GlcNS6S IdoA2S GlcNS6S IdoA2S GlcNS6S IdoA2S GlcNS6S IdoA2S GlcNS6S I2S6 I2S6 I2S6 I2S6 I2S6 b c Figure 1 Structure of heparan sulfate. (a) Chemical structure of a heparin-derived decasaccharide. Carbon numbers of the modification sites are indicated in red. (b) Stereo view of a heparin-derived decasaccharide in space-filling representation, based on Protein Data Bank identifier 1E0O, with carbon in gray, oxygen in red, nitrogen in blue, and sulfate in yellow. (c) Stereo view of the same decasaccharide in stick representation. Note the helical nature of the chain and the alternating clusters of three sulfates groups on each side of the sugar backbone. Abbreviations: GlcNS, N-sulfoglucosamine; IdoA, L-iduronic acid. size, composition, and distribution of the NS Importantly, the terms heparan and heparin domains vary significantly. Unlike DNA, RNA, are often used interchangeably, which is incor- Annu. Rev. Biochem. 2014.83:129-157. Downloaded from www.annualreviews.org and protein assembly, the assembly of HS is rect. HS occurs naturally in all cells and varies Access provided by University of California - San Diego on 06/23/20. For personal use only. not template driven. Thus, the organization enormously in terms of degree of sulfation and and specificity of the biosynthetic enzymes, chain length, which depend on its biological availability of precursors, and flux through the origin. The chains typically consist of 50 to Golgi apparatus are thought to determine chain 250 disaccharide units (20–100 kDa). In length, degree of sulfation, and epimerization, contrast, heparin is a degradation product as well as the size and spacing of the sulfated derived from HS isolated from porcine entrails domains. The assembly and degradation of HS or equine lung and typically consists of chains have been reviewed elsewhere and are not con- ranging from 12 to 14 kDa. Heparin contains sidered further herein (10–13). What dictates larger NS domains and the extent of modifica- the size and composition of HS in different cells tion is greater, giving rise to large sections of at different times in development remains one the chains containing fully sulfated (trisulfated) of the great enigmas in modern cell biology. disaccharides and IdoA (Table 1 summarizes www.annualreviews.org • Heparan Sulfate–Binding Protein 131 BI83CH06-Esko ARI 3 May 2014 10:35 charge of the chains also endows heparin with HEPARAN SULFATE PROTEOGLYCAN potent nonspecific cation-exchange properties. Thus, the fact that a protein binds to heparin HS proteoglycans (HSPGs) consist of a core protein and one or does not necessarily mean that it also binds to more covalently linked HS chains. Of the 17 HSPGs that have HS. been identified so far, many are membrane associated through The purpose of this review is to provide an either a transmembrane domain (syndecans 1–4, CD44v3, overview of HSBPs and the various ways in neuropilin, betaglycan) or a GPI anchor (glypicans 1–6). which these proteins interact with HS or hep- Several HSPGs, including collagen XVIII, agrin, and perlecan, arin, drawing on specific examples that illustrate are secreted into the extracellular matrix. One proteoglycan, underlying biochemical and structural princi- serglycin, is located in the cytoplasmic secretory granules of ples. Many bacteria and viruses also express endothelial, endocrine, and hematopoietic cells. Whether the HSBPs and are discussed elsewhere (14, 15). identity of the core protein affects the structure of HS remains For brevity, we discuss mostly eukaryotic HS- unresolved. The core proteins of HSPGs are not merely carriers BPs for which the HS-binding
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