A Useful Guide to Lectin Binding: Machine-Learning Directed Annotation of 57 Unique Lectin Specificities

ACS Chemical Biology, Journal Year: 2022, Volume and Issue: 17(11), P. 2993 - 3012

Published: Jan. 27, 2022

Glycans are critical to every facet of biology and medicine, from viral infections embryogenesis. Tools study glycans rapidly evolving; however, the majority our knowledge is deeply dependent on binding by glycan proteins (e.g., lectins). The specificities lectins, which often naturally isolated proteins, have not been well-defined, making it difficult leverage their full potential for analysis. Herein, we use a combination machine learning algorithms expert annotation define lectin specificity this important probe set. Our analysis uses comprehensive microarray commercially available lectins obtained using version 5.0 Consortium Functional Glycomics (CFGv5). This data set was made public in 2011. We report creation its large-scale evaluation lectin-glycan behaviors. motif performed integrating 68 manually defined features with systematic probing computational rules significant motifs mono- disaccharides linkages. Combining manual annotation, create detailed interpretation glycan-binding 57 unique categorized major motifs: mannose, complex-type N-glycan, O-glycan, fucose, sialic acid sulfate, GlcNAc chitin, Gal LacNAc, GalNAc. work provides fresh insights into complex current use, providing guide these reagents.

Language: Английский

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Siglec-9 acts as an immune-checkpoint molecule on macrophages in glioblastoma, restricting T-cell priming and immunotherapy response

Nature Cancer, Journal Year: 2023, Volume and Issue: 4(9), P. 1273 - 1291

Published: July 17, 2023

Language: Английский

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Aberrant Sialylation in Cancer: Therapeutic Opportunities

Cancers, Journal Year: 2022, Volume and Issue: 14(17), P. 4248 - 4248

Published: Aug. 31, 2022

The surface of every eukaryotic cell is coated in a thick layer glycans that acts as key interface with the extracellular environment. Cancer cells have different ‘glycan coat’ to healthy and aberrant glycosylation universal feature cancer linked all hallmarks. This means hold huge potential for development new diagnostic therapeutic strategies. One change tumour increased sialylation, both on N-glycans O-glycans, which leads dense forest sialylated structures covering surface. hypersialylation has far-reaching consequences cells, are fundamental growth, metastasis, immune evasion drug resistance. strategies inhibit sialylation represents an important opportunity develop therapeutics. Here, I summarise recent advances target cancer, including sialyltransferase inhibitors Siglecs Selectins, discuss opportunities future.

Language: Английский

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Targeting the Siglec–sialic acid axis promotes antitumor immune responses in preclinical models of glioblastoma

Science Translational Medicine, Journal Year: 2023, Volume and Issue: 15(705)

Published: July 19, 2023

Glioblastoma (GBM) is the most aggressive form of primary brain tumor, for which effective therapies are urgently needed. Cancer cells capable evading clearance by phagocytes such as microglia- and monocyte-derived through engaging tolerogenic programs. Here, we found that high expression sialic acid–binding immunoglobulin-like lectin 9 (Siglec-9) correlates with reduced survival in patients GBM. Using cell-specific knockouts Siglec-E, murine functional homolog Siglec-9, together single-cell RNA sequencing, demonstrated Siglec-E inhibits phagocytosis these cells, thereby promoting immune evasion. Loss on further enhanced antigen cross-presentation production pro-inflammatory cytokines, resulted more efficient T cell priming. This bridging innate adaptive responses delayed tumor growth prolonged models Furthermore, showed combinatorial activity blockade other immunotherapies demonstrating potential targeting Siglec-9 a treatment

Language: Английский

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Deep mutational scanning of H5 hemagglutinin to inform influenza virus surveillance

PLoS Biology, Journal Year: 2024, Volume and Issue: 22(11), P. e3002916 - e3002916

Published: Nov. 12, 2024

H5 influenza is considered a potential pandemic threat. Recently, viruses belonging to clade 2.3.4.4b have caused large outbreaks in avian and multiple nonhuman mammalian species. Previous studies identified molecular phenotypes of the viral hemagglutinin (HA) protein that contribute humans, including cell entry, receptor preference, HA stability, reduced neutralization by polyclonal sera. However, prior experimental work has only measured how these are affected handful >10,000 different possible amino-acid mutations HA. Here, we use pseudovirus deep mutational scanning measure all affect each phenotype. We identify allow better bind α2-6-linked sialic acids show some already carry stabilize also sera from mice ferrets vaccinated against or infected with viruses. These antigenic maps enable rapid assessment when new strains acquired may create mismatches candidate vaccine virus, mutation present recent HAs causes change. Overall, systematic nature combined safety pseudoviruses enables comprehensive measurements phenotypic effects can inform real-time interpretation variation observed during surveillance influenza.

Language: Английский

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The avian and human influenza A virus receptors sialic acid (SA)-α2,3 and SA-α2,6 are widely expressed in the bovine mammary gland

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 3, 2024

Abstract An outbreak of H5N1 highly pathogenic influenza A virus (HPIAV) has been detected in dairy cows the United States. Influenza (IAV) is a negative-sense, single-stranded, RNA that not previously associated with widespread infection cattle. As such, cattle are an extremely under-studied domestic IAV host species. receptors on cells sialic acids (SAs) bound to galactose either α2,3 or α2,6 linkage. Human IAVs preferentially bind SA-α2,6 (human receptor), whereas avian have preference for (avian receptor). The receptor can further be divided into two receptors: isolated from chickens generally more tightly SA-α2,3-Gal-β1,4 (chicken duck SA-α2,3-Gal-β1,3 (duck We found all were expressed, different degree, mammary gland, respiratory tract, and cerebrum beef and/or human widely expressed bovine chicken dominated tract. In general, only low expression was observed neurons cerebrum. These results provide mechanistic rationale high levels reported infected milk show potential act as mixing vessel novel generation. Graphical abstract Created Biorender.com

Language: Английский

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Pancreatic cancer-associated fibroblasts modulate macrophage differentiation via sialic acid-Siglec interactions

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: April 9, 2024

Abstract Despite recent advances in cancer immunotherapy, pancreatic ductal adenocarcinoma (PDAC) remains unresponsive due to an immunosuppressive tumor microenvironment, which is characterized by the abundance of cancer-associated fibroblasts (CAFs). Once identified, CAF-mediated immune inhibitory mechanisms could be exploited for immunotherapy. Siglec receptors are increasingly recognized as checkpoints, and their ligands, sialic acids, known overexpressed cells. Here, we unveil a previously unrecognized role acid-containing glycans on PDAC CAFs crucial modulators myeloid Using multiplex immunohistochemistry transcriptomics, show that stroma enriched compared cells normal fibroblasts, ST3GAL4 expression. We demonstrate acids CAF cell lines serve ligands Siglec-7, -9, -10 -15, distinct from cells, these found biopsies. Furthermore, drive differentiation monocytes tumor-associated macrophages vitro, sialylation plays dominant this process sialylation. Collectively, our findings unravel mechanism immunomodulation, may provide targets immunotherapy PDAC.

Language: Английский

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Display of the human mucinome with defined O-glycans by gene engineered cells

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: July 1, 2021

Abstract Mucins are a large family of heavily O-glycosylated proteins that cover all mucosal surfaces and constitute the major macromolecules in most body fluids. primarily defined by their variable tandem repeat (TR) domains densely decorated with different O-glycan structures distinct patterns, these arguably convey much informational content mucins. Here, we develop cell-based platform for display production human TR O-glycodomains (~200 amino acids) tunable patterns O-glycans using membrane-bound secreted reporters expressed glycoengineered HEK293 cells. Availability mucin advances experimental studies into versatile role mucins at interface pathogenic microorganisms microbiome, sparks new strategies molecular dissection specific roles adhesins, glycoside hydrolases, glycopeptidases, viruses other interactions TRs as highlighted examples.

Language: Английский

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Sialic acid O-acetylation: From biosynthesis to roles in health and disease

Journal of Biological Chemistry, Journal Year: 2021, Volume and Issue: 297(2), P. 100906 - 100906

Published: June 19, 2021

Sialic acids are nine-carbon sugars that frequently cap glycans at the cell surface in cells of vertebrates as well certain types invertebrates and bacteria. The backbone sialic can undergo extensive enzymatic modification nature O-acetylation C-4/7/8/9 position particular is widely observed. In recent years, detection analysis O-acetylated have advanced, acid-specific O-acetyltransferases (SOATs) O-acetylesterases (SIAEs) add remove O-acetyl groups, respectively, been identified characterized mammalian cells, invertebrates, bacteria, viruses. These advances now allow us to draw a more complete picture biosynthetic pathway diverse drive generation genetically biochemically engineered model lines organisms with altered expression for dissection their roles glycoprotein stability, development, immune recognition, discovery novel functions. Furthermore, growing number studies associate acid cancer, autoimmunity, infection, providing rationale development selective probes inhibitors SOATs SIAEs. Here, we discuss current insights into biosynthesis biological functions review evidence linking this disease. emerging strategies design, synthesis, potential application unnatural SIAEs may enable therapeutic targeting versatile modification. Sugars serve essential molecular building blocks assemble complex numerous (1Marth J.D. A unified vision life.Nat. Cell Biol. 2008; 10: 1015-1016Crossref PubMed Scopus (0) Google Scholar). Virtually every produces glycans; short, long, linear, branched structures composed different sugar molecules attached membrane secreted glycoproteins glycolipids. vast collection produced by or tissue referred “the glycome” (2Schjoldager K.T. Narimatsu Y. Joshi H.J. Clausen H. Global view human protein glycosylation pathways functions.Nat. Rev. Mol. 2020; 21: 729-749Crossref (59) vertebrate assembled inside endoplasmic reticulum, Golgi system, nucleus, cytoplasm, mitochondria where over 200 glycosyltransferase enzymes build glycome Scholar, 3Narimatsu Nason R. Van Coillie J. Karlsson Sun L. Ye Z. Chen Y.H. Schjoldager Steentoft C. Furukawa S. Bensing B.A. Sullam P.M. Thompson A.J. Paulson J.C. et al.An Atlas enables display gene cells.Mol. Cell. 2019; 75: 394-407Abstract Full Text PDF (65) regulates multitude processes, such functional biochemical properties proteins lipids, cellular adhesion, communication, recognition events (4Varki A. Biological glycans.Glycobiology. 2017; 27: 3-49Crossref (784) Important determinants (Sias) reside terminal some pathogens. family comprises >80 naturally occurring members related nonulosonic acids, α-keto found (5Varki Schnaar R.L. Schauer other acids.in: Essentials Glycobiology. 3rd Ed. Cold Spring Harbor Laboratory, Harbor, NY2015: 179-195Google 6Schauer Kamerling J.P. Exploration world.Adv. Carbohydr. Chem. Biochem. 2018; 1-213Crossref (67) 7Angata T. Varki Chemical diversity alpha-keto acids: An evolutionary perspective.Chem. 2002; 102: 439-469Crossref (974) Regarding large diversity, assembly acid-carrying (sialoglycans) forms subclass within glycome—the sialome (8Cohen M. sialome--far than sum its parts.OMICS. 2010; 14: 455-464Crossref include protection from proteases (9Aquino D. Wong Margolis R.U. R.K. residues inhibit proteolytic degradation dopamine beta-hydroxylase.FEBS Lett. 1980; 112: 195-198Crossref 10Gorog P. Pearson moieties on protect endothelial damage.J. Pathol. 1985; 146: 205-212Crossref Scholar); regulation serum half-life erythrocytes cleared liver upon desialylation (11Morell A.G. Gregoriadis G. Scheinberg I.H. Hickman Ashwell role determining survival circulation.J. 1971; 246: 1461-1467Abstract 12Sorensen A.L. Rumjantseva V. Nayeb-Hashemi Hartwig J.H. Wandall H.H. Hoffmeister K.M. Role platelet life span: Exposure beta-galactose results rapid clearance platelets circulation asialoglycoprotein receptor-expressing macrophages hepatocytes.Blood. 2009; 114: 1645-1654Crossref (137) 13Yang W.H. Aziz P.V. Heithoff D.M. Mahan M.J. Smith J.W. Marth intrinsic mechanism aging turnover.Proc. Natl. Acad. Sci. U. 2015; 13657-13662Crossref (60) likely formation blood vessel lumen (14Strilic B. Eglinger Krieg Zeeb Axnick Babal Muller D.J. Lammert E. Electrostatic cell-surface repulsion initiates developing vessels.Curr. 20: 2003-2009Abstract (89) sialoglycans sialyl Lewisx contribute trafficking via binding selectins endothelium (15McEver R.P. Moore K.L. Cummings R.D. Leukocyte mediated selectin-carbohydrate interactions.J. 1995; 270: 11025-11028Abstract (574) Scholar), they form ligands immunomodulatory Siglec receptors set threshold activation (16Macauley M.S. Crocker P.R. Siglec-mediated function disease.Nat. Immunol. 2014; 653-666Crossref (466) 17Büll Heise Adema G.J. Boltje T.J. mimetics target acid-siglec Axis.Trends 2016; 41: 519-531Abstract (70) also sites pathogens be utilized microorganisms mimicry (18Heise Langereis Rossing de Jonge M.I. Büll Selective inhibition acid-based Haemophilus influenzae abrogates resistance.Cell 25: 1279-1285.e1278Abstract (3) 19Stencel-Baerenwald J.E. Reiss K. Reiter Stehle Dermody T.S. sweet spot: Defining virus-sialic interactions.Nat. Microbiol. 12: 739-749Crossref (168) aberrant sialoglycan associated tumor growth, evasion, metastasis (20Büll Stoel M.A. den Brok M.H. sweeten tumor's life.Cancer Res. 74: 3199-3204Crossref (220) 21van Wall Santegoets K.C.M. van Houtum E.J.H. Sialoglycans Siglecs shape microenvironment.Trends 274-285Abstract (27) 22Pearce O.M. Laubli cancer biology immunity.Glycobiology. 26: 111-128Crossref (192) versatility reflected structural arises natural modifications (Fig. 1A) linkages (α2-3/6/8) underlying glycoconjugates (N-/O-glycans, glycolipids). most prevalent derivative humans N-acetylneuraminic (Neu5Ac), notable derivatives 2-keto-3-deoxynononic (KDN) N-glycolylneuraminic (Neu5Gc) Interestingly, lost ability biosynthesize Neu5Gc due mutation CMP-Neu5Ac hydroxylase (CMAH) (23Chou Takematsu Diaz Iber Nickerson Wright Muchmore E.A. Nelson D.L. Warren S.T. CMP-sialic occurred after Homo-Pan divergence.Proc. 1998; 95: 11751-11756Crossref (411) however, scavenged exogenous, dietary sources, low amounts incorporated (24Tangvoranuntakul Gagneux Bardor N. Human uptake incorporation an immunogenic nonhuman acid.Proc. 2003; 100: 12045-12050Crossref (434) Further any hydroxyl amine groups result distinct known date (6Schauer Analysis these samples challenging, often not fully understood. Presumably, Sia race between host exploit infection. line Red Queen hypothesis, concept which species must constantly adapt survive competition evolving pathogens, evolved abrogate pathogen interactions while preserving overall endogenous (25Varki Nothing glycobiology makes sense, except light evolution.Cell. 2006; 126: 841-845Abstract (180) Moreover, additional regulatory informational cues advantageous host. common addition one esters yielding about 20 O-Ac-Sias (26Mandal Schwartz-Albiez Vlasak Functions acids.Top. Curr. 366: 1-30PubMed Due identification viruses, many aspects regarding disease recently uncovered, anticipate pace will continue. understanding health implications applications inhibitors. Soon Blix Klenk (27Blix Über die Kohlenhydratgruppen des Submaxillarismucins.Z. Physiol. 1936; 240: 43-54Crossref 28Klenk Neuraminsäure, das Spaltprodukt eines neuen Gehirnlipoids.Z. 1941; 268: 50-58Crossref presence was noted, among others, succeeded verification using mass spectrometry 29Kamerling Vliegenthart J.F. Identification O-cetylated N-acylneuraminic spectrometry.Carbohydr. 1975; 7-17Crossref occur C-4, C-7, C-8, C-9 1A). denoted exemplified Neu5Ac (which carries N-acetyl group C-5) Neu4,5Ac2, Neu5,7Ac2, Neu5,8Ac2, Neu5,9Ac2, respectively (30Varki Aebi Packer N.H. Seeberger P.H. Esko Stanley Hart Darvill Kinoshita Prestegard J.J. Freeze Bertozzi C.R. al.Symbol nomenclature graphical representations 1323-1324Crossref (448) simultaneously multiple positions, giving rise di- tri-O-acetylated Sias Neu5,7,9Ac3 Neu5,7,8,9Ac4, respectively. overview provided Varki, Schauer, Kamerling, who made seminal contributions 31Varki Roland (1936-2019): tribute “Mr. acid”.Glycobiology. 30: 132-133Crossref static, spontaneous migration glycerol chain occur, but C-4 (32Kamerling Shukla A.K. Stoll Halbeek Migration N,O-acetylneuraminic acids.Eur. 1987; 162: 601-607Crossref At neutral slightly basic pH, bidirectional along tail observed 33Ji Sasmal Li W. Oh Srivastava Hargett A.A. Wasik B.R. Yu Choudhury Parrish Freedberg D.I. Wang L.P. X. Reversible side influence recognition.ACS 2021; https://doi.org/10.1021/acschembio.0c00998Crossref (1) addition, di-O-acetyl-Sia Neu5,8,9Ac3 has indicated 34Varki release purification glycoconjugates: Methods minimize loss groups.Anal. 1984; 137: 236-247Crossref proceeds intramolecularly through orthoester intermediates, mainly takes place mild pH it stabilizes mildly acidic <5 Recent sample preparation O-Ac-Sia provide opportunity address process acetyl (35Wu Zhang Q. Liu Zheng Characterization MALDI-MS combination methylamidation permethylation.Sci. Rep. 7: 46206Crossref (10) 36Khedri Xiao Landig C.S. chemical solution problems studying biologically important unstable 9-O-acetyl acids.ACS 214-224Crossref 37Li Battistel M.D. Reeves combined NMR, MD DFT conformational acid-containing GM3 ganglioside glycan 9-N-acetyl mimic.Glycobiology. 787-801Crossref starts novo cytoplasm several steps derived exogenous sources (e.g., dietary) (38Freeze G.W. Glycosylation precursors.in: 51-63Google 39Moons S.J. Derks M.T. glycoengineering N-acetylmannosamine analogs.Glycobiology. 29: 433-445PubMed activated nucleus conjugation cytidine 5′-monophosphate (CMP) transported system sialyltransferase isoenzymes use donor incorporate glycosidic 40Harduin-Lepers Vallejo-Ruiz Krzewinski-Recchi Samyn-Petit Julien Delannoy family.Biochimie. 2001; 83: 727-737Crossref (402) involves activity esterases Scholar) 1B). So far, single SOAT (CASD1, capsule structure1 domain containing 1) (41Arming Wipfler Mayr Merling Vilas Cas1 protein: O-acetyltransferase?.Glycobiology. 2011; 553-564Crossref (40) 42Baumann A.M. Bakkers Buettner F.F. Hartmann Grove Groot R.J. Muhlenhoff 9-O-Acetylation catalysed CASD1 covalent acetyl-enzyme intermediate.Nat. Commun. 6: 7673Crossref sialic-acid-specific esterase (SIAE) (43Guimaraes Bazan Castagnola Copeland N.G. Gilbert Jenkins N.A. Zlotnik Molecular cloning characterization lysosomal O-acetylesterase.J. 1996; 271: 13697-13705Abstract 44Orizio F. Damiati Giacopuzzi Benaglia Pianta Borsani Bresciani Monti esterase: Towards better puzzling enzyme.Glycobiology. 992-1006Crossref (8) 45Takematsu Stoddart Lysosomal cytosolic 9-O-acetylesterase activities Be encoded differential usage signal peptide-encoding exon N terminus.J. 1999; 274: 25623-25631Abstract (31) 46Stoddart Paige C.J. cDNA encoding murine RNA hematopoietic non-hematopoietic origin.Nucleic Acids 24: 4003-4008Crossref 47Butor Higa Structural, immunological, O-acetylesterase rat liver.J. 1993; 10207-10213Abstract (Table 1). Especially remained challenging decades lability intact enzyme during (48Butor High level N-linked oligosaccharides membranes. Differential subcellular distribution 7- involved regulation.J. 10197-10206Abstract 49Lrhorfi L.A. Srinivasan G.V. Properties partial sialate-O-acetyltransferase bovine submandibular glands.Biol. 2007; 388: 297-306Crossref 50Ogura Nara Watanabe Kohno Tai Sanai Cloning GD3 ganglioside.Biochem. Biophys. 225: 932-938Crossref 51Kanamori Nakayama Fukuda M.N. Stallcup W.B. Sasaki Hirabayashi Expression required ganglioside: putative acetyl-CoA transporter.Proc. 1997; 94: 2897-2902Crossref 52Shi W.X. Chammas Induction 9-O-acetylation products: Implications O-acetyltransferases.Glycobiology. 8: 199-205Crossref Eventually, SIAE cloned 1996 whereas 2011 data mining genome acetyltransferase genes unknown 2015 (42Baumann Scholar).Table 1Occurrence microorganismsSpeciesO-Ac-Sia formSOATSIAEO-Ac-Sia GBPReferencesHomo sapiensDiverse 1C)CASD1SIAEnd(41Arming 43Guimaraes Scholar)Campylobacter jejuniNeu5,9Ac2 (α2-8-linked)aCapsular O-Ac-Sia.Orf11ndnd(190Houliston R.S. Endtz H.P. Yuki Jarrell H.C. Koga Belkum Karwaski M.F. Wakarchuk W.W. sialate O-acetyltransferase Campylobacter jejuni: Demonstration direct transfer terminalalpha-2, 8-linked acid.J. 281: 11480-11486Abstract Scholar)Escherichia coli K1Neu5,7/9Ac2 (α2-3/8-linked)aCapsular O-Ac-Sia.NeuO NeuDNeuAnd(194Higa Acetyl-coenzyme A:polysialic K1-positive Escherichia coli. responsible plus phenotype variation.J. 1988; 263: 8872-8878Abstract 195Deszo E.L. Steenbergen S.M. Vimr E.R. K1 polysialic gene, neuO, variation involving mobile contingency locus.Proc. 2005; 5564-5569Crossref 196Schulz E.C. Bergfeld Ficner Crystal structure specific NeuO.PLoS One. 6e17403Crossref (11) 197Bergfeld Claus Vogel Mühlenhoff Biochemical thepolysialic NeuO K1.J. 282: 22217-22227Abstract 198Steenbergen Lee Y.C. Vann W.F. Vionnet L.F. Separate O acetylation polymeric monomeric Bacteriol. 188: 6195-6206Crossref (51) Scholar)Enterohemorrhagic (EHEC)Neu5,9Ac2NANanS NanS-pnd(167Feuerbaum Saile Pohlentz Muthing Schmidt De-O-Acetylation mucin-derived recombinant NanS-p O157:H7 strain EDL933.Int. Med. 308: 1113-1120Crossref (5) 168Saile Schwarz Eissenberger Klumpp Fricke F.W. Growth advantage O104:H4 strains 5-N-acetyl-9-O-acetyl neuraminic carbon source dependent heterogeneous phage-Borne nanS-p esterases.Int. 459-468Crossref (6) 169Rangara

Language: Английский

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Siglec Ligands

Cells, Journal Year: 2021, Volume and Issue: 10(5), P. 1260 - 1260

Published: May 20, 2021

A dense and diverse array of glycans on glycoproteins glycolipids decorate all cell surfaces. In vertebrates, many these carry sialic acid, in a variety linkages glycan contexts, as their outermost sugar moiety. Among functions, engage complementary binding proteins (lectins) to regulate physiology. the are Siglecs, acid immunoglobulin-like lectins. humans, there 14 most which expressed overlapping subsets immune system cells. Each Siglec engages distinct, endogenous sialylated that initiate signaling programs cellular responses. Here, we explore emerging science ligands, including sialoglycoproteins synthetic sialomimetics. Knowledge this field promises reveal new molecular pathways controlling physiology opportunities for therapeutic intervention.

Language: Английский

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