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Exploring Functional Pairing Between Surface Glycoconjugates And Exploring functional pairing between surface PNAS PLUS glycoconjugates and human galectins using programmable glycodendrimersomes Qi Xiaoa, Anna-Kristin Ludwigb, Cecilia Romanòc, Irene Buzzaccheraa,d,e,f, Samuel E. Shermana, Maria Vetroc, Sabine Vértesyb, Herbert Kaltnerb, Ellen H. Reedg, Martin Möllerd,e, Christopher J. Wilsonf, Daniel A. Hammerg,h, Stefan Oscarsonc, Michael L. Kleini,1, Hans-Joachim Gabiusb, and Virgil Perceca,1 aRoy & Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323; bInstitute of Physiological Chemistry, Faculty of Veterinary Medicine, Ludwig-Maximilians-University, 80539 Munich, Germany; cCentre for Synthesis and Chemical Biology, University College Dublin, Dublin 4, Ireland; dDWI − Leibniz Institute for Interactive Materials, RWTH Aachen University, 52074 Aachen, Germany; eInstitute of Technical and Macromolecular Chemistry, RWTH Aachen University, 52074 Aachen, Germany; fNovioSense B.V., 6534 AT Nijmegen, The Netherlands; gDepartment of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104-6321; hDepartment of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA 19104-6391; and iInstitute of Computational Molecular Science, Temple University, Philadelphia, PA 19122 Contributed by Michael L. Klein, January 4, 2018 (sent for review November 16, 2017; reviewed by Timothy J. Deming and Yoshiko Miura) Precise translation of glycan-encoded information into cellular lection process are not yet defined quantitatively. Confronted with activity depends critically on highly specific functional pairing the combination of natural glycan complexity and the result of between glycans and their human lectin counter receptors. Sulfo- evolutionary structure diversification within a lectin family, the glycolipids, such as sulfatides, are important glycolipid components ultimate experimental strategy would seem to require full glycome of the biological membranes found in the nervous and immune and lectin network analysis. systems. The optimal molecular and spatial design aspects of Although chemical control of glycoengineering of cells by insert- sulfated and nonsulfated glycans with high specificity for lectin- ing glycopolymers (14–22) into membranes was previously reported mediated bridging are unknown. To elucidate how different molec- (23, 24), to date, much research in the field of glycan−lectin CHEMISTRY ular and spatial aspects combine to ensure the high specificity of matchmaking has focused on answering the question posed decades lectin-mediated bridging, a bottom-up toolbox is devised. To this ago, namely: Are glycan molecules in search of a function (25)? end, negatively surface-charged glycodendrimersomes (GDSs), of These experiments are making us aware that our understanding of different nanoscale dimensions, containing sulfo-lactose groups are the factors governing the high specificity of pairing glycoconjugates self-assembled in buffer from a synthetic sulfatide mimic: Janus with lectins is still very limited (26, 27) despite its broad impact on ′ O glycodendrimer (JGD) containing a 3 - -sulfo-lactose headgroup. cell physiology (28). Also prepared for comparative analysis are GDSs with nonsulfated Accordingly, here we employ an approach based on model lactose, a common epitope of human membranes. These self- systems to begin to tackle this formidable problem. In essence, self- PHYSIOLOGY assembled GDSs are employed in aggregation assays with 15 galec- assembled nanovesicles having programmable surfaces presenting tins, comprising disease-related human galectins, and other natural sugar moieties are used in combination with natural and engi- and engineered variants from four families, having homodimeric, neered lectins to explore the complexity of glycan−lectin specific- heterodimeric, and chimera architectures. There are pronounced dif- ity. The nanovesicle toolbox comprises Janus glycodendrimers ferences in aggregation capacity between human homodimeric and heterodimeric galectins, and also with respect to their responsive- ness to the charge of carbohydrate-derived ligand. Assays reveal Significance strong differential impact of ligand surface charge and density, as well as lectin concentration and structure, on the extent of surface Cells are decorated with charged and uncharged carbohydrate cross-linking. These findings demonstrate how synthetic JGD- ligands known as glycans, which are responsible for several key headgroup tailoring teamed with protein engineering and network functions, including their interactions with proteins known as assays can help explain how molecular matchmaking operates in the lectins. Here, a platform consisting of synthetic nanoscale vesi- cellular context of glycan and lectin complexity. cles, known as glycodendrimersomes, which can be programmed with cell surface-like structural and topological complexity, is glycodendrimers | glycolipids | aggregation employed to dissect design aspects of glycan presentation, with specificity for lectin-mediated bridging. Aggregation assays re- he enormous potential of glycans of cellular glycoconjugates veal the extent of cross-linking of these biomimetic nanoscale — to serve as biological messengers has spurred efforts to map vesicles presenting both anionic and neutral ligands in a bio- T — the glycome (1–4). In parallel, work with synthetic multivalent active manner with disease-related human and other galectins, thus offering the possibility of unraveling the nature of these carbohydrates and neoglycoconjugates is revealing that topo- fundamental interactions. logical features of glycan presentation on a scaffold such as protein, lipid, or microdomain come into play when these mes- Author contributions: M.L.K., H.-J.G., and V.P. designed research; Q.X., A.-K.L., C.R., I.B., sages are “read” by endogenous receptors known as lectins (5–9). S.E.S., M.V., and E.H.R. performed research; M.V., S.V., M.M., C.J.W., D.A.H., and S.O. A similar situation likely obtains for the “readers.” This com- contributed new reagents/analytic tools; Q.X., I.B., S.E.S., H.K., S.O., M.L.K., H.-J.G., plementarity ensures that the functional pairing, which is of and V.P. analyzed data; and M.L.K., H.-J.G., and V.P. wrote the paper. broad physiological significance, especially for cell surface phe- Reviewers: T.J.D., University of California, Los Angeles; and Y.M., Kyushu University. nomena, achieves the desired specificity (10, 11). Cell adhesion The authors declare no conflict of interest. and bridging often critically depend on glycan−lectin recognition, This open access article is distributed under Creative Commons Attribution-NonCommercial- NoDerivatives License 4.0 (CC BY-NC-ND). and stringent nonpromiscuous selection occurs when forming pairs 1To whom correspondence may be addressed. Email: [email protected] or percec@sas. despite the vast diversity of glycoconjugates, as, for example, with upenn.edu. the C-type lectins and for the cell adhesion selectins (12, 13). This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. However, the underlying structural parameters governing the se- 1073/pnas.1720055115/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1720055115 PNAS Latest Articles | 1of10 Downloaded by guest on October 3, 2021 (JGDs) with various sugar headgroups obtained by synthesis. JGD mental scope. These Lac and suLac-presenting GDSs mimic the design enables control of glycan presentation/density and diversity, surface of biological membranes containing natural sulfatides eventually mimicking structural and topological features encoun- and galactocerebrosides (Fig. S1A) and are formed by the tered on cell surfaces. As proof-of-principle, the nanovesicle self-assembly of sequence-defined JGDs without the need of toolbox is employed to couple with adhesion/growth-regulatory coassembly of glycolipids with phospholipids. Specifically, the galectins (Gals). GDSs (36, 37) are prepared by simple injection of JGDs in This family of lectins has been selected because of its potent buffer. The aggregation of GDSs by galectins provides the bridging activity (29–31). Structurally, the lectins are grouped most direct, simple, and convenient method to evaluate the into the three categories shown in Fig. 1A, often present as a trans-bridging by increased UV-vis turbidity (Fig. S1B). network in human tissues (32–35). In each case, i.e., the homo- The cis activity of galectins is not accessible by this simple dimer, the linker-associated heterodimer, and the chimera-type method since, unlike cell membranes, GDSs do not provide monomer capable of self-aggregation (Fig. 1A), the protein de- biosignals. sign enables nanovesicles−counterreceptor cross-linking. Since results of current research demonstrate that each family member Results and Discussion appears to have its own activity profile with emerging cases of The Lectin Toolbox. The test panel represents the three natural functional antagonism, cooperation, and redundancy, bridging types of design of human galectins, in general terms shown in Fig. activities are likely to differ and respond differently to features of 1A. In detail, it consists of a noncovalently associated homodimer ligand display. In principle, each is relevant to make functional (Gal-1; Fig. 1B), two cases of linker-connected heterodimer (Gal- pairing possible. 4inFig.1C, and Gal-8 in Fig. 1D) and the chimera-type Gal-3 To test this hypothesis and gain insights into the mutual re- (Fig. 1E). It is built
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