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Structural Basis for Simultaneous Recognition of an O-Glycan and Its Attached Peptide of Mucin Family by Immune Receptor Pilrα

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Structural Basis for Simultaneous Recognition of an O-Glycan and Its Attached Peptide of Mucin Family by Immune Receptor Pilrα Structural basis for simultaneous recognition of an O-glycan and its attached peptide of mucin family by immune receptor PILRα Kimiko Kurokia,1, Jing Wangb,1,2, Toyoyuki Osea,1, Munechika Yamaguchic,1, Shigekazu Tabatac,1, Nobuo Maitac, Seiko Nakamurac, Mizuho Kajikawac, Amane Kogureb,3, Takeshi Satohb,4, Hisashi Araseb,d,e,5, and Katsumi Maenakaa,e,5 aFaculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan; bDepartment of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan; cMedical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan; dLaboratory of Immunochemistry, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan; and eCore Research for Evolutionary Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan Edited by Pamela J. Bjorkman, California Institute of Technology, Pasadena, CA, and approved May 6, 2014 (received for review December 28, 2013) Paired Ig-like type 2 receptor α (PILRα) recognizes a wide range of recognizing O-glycosylated ligand family (8). All PILR ligands O-glycosylated mucin and related proteins to regulate broad im- are mucin or have mucin-like domains in which the heavy mune responses. However, the molecular characteristics of these O-glycosylation occurs and which are significantly important for recognitions are largely unknown. Here we show that sialylated a wide range of cell–cell interactions. Furthermore, PILRs show O-linked sugar T antigen (sTn) and its attached peptide region are unique features for recognizing not only O-linked sugars but also both required for ligand recognition by PILRα. Furthermore, we the peptide sequences attached to the sugars. determined the crystal structures of PILRα and its complex with PILRs are expressed broadly on immune-related cells, including an sTn and its attached peptide region. The structures show that monocytes/macrophages, dendritic cells, B cells, natural killer PILRα exhibits large conformational change to recognize simulta- (NK) cells, and neutrophils, as well as on neurons (6). A recent neously both the sTn O-glycan and the compact peptide structure study showed that PILRs are important for the control of acute constrained by proline residues. Binding and functional assays sup- Streptococcus aureus infection in the lung in vivo (9). Moreover, port this binding mode. These findings provide significant insight we recently demonstrated that in Pilra-deficient mice neutrophil into the binding motif and molecular mechanism (which is distinct infiltration was increased at the LPS-induced inflammatory sites from sugar-recognition receptors) by which O-glycosylated mucin by increased adhesion to the β2 integrin and that these mice were proteins with sTn modifications are recognized in the immune highly susceptible to endotoxin shock (10). These findings in- system as well as during viral entry. dicate that PILRα is relevant for the regulation of neutrophil recruitment in inflammatory responses, clearly demonstrating paired receptor | O-glycosylated protein | X-ray crystallography | the importance of PILRα in innate immune responses. Mouse immune regulation Significance ucin-type O-glycosylation is highly important in physio- Mlogical events, but it is too complicated to be fully un- O O Here we show that both sialylated -linked sugar T antigen derstood because the structures of modified -linked sugars are (sTn) and its attached peptide are required for recognition basically heterogeneous and are extremely difficult to predict. of paired immunoglobulin-like type 2 receptor α (PILRα)by However, this complexity is beneficial in discriminating cellular O-glycosylated mucin and related proteins. The crystal struc- conditions. To date, a number of molecules have been shown to α O O ture of PILR complexed with the -glycosylated peptide rea- recognize -glycans, which are important in many biological sonably explains this simultaneous recognition of both the sTn events, including tumorigenesis and immune evasion (1), as well O O -glycan and the compact peptide structure, distinct from other as infectious diseases. Selectins recognize the -glycan parts of sugar-recognition receptors. The structure provides a novel mucin-type glycoproteins on target cell surfaces to regulate the framework for the receptor-binding mode of O-glycosylated rolling and attachment of lymphocytes in inflammation and in mucin proteins, which are relevant in immune responses and O cancer metastasis. However, how -glycosylated proteins are viral infection. recognized by specific receptors has remained largely unclear. To regulate function, the immune system has a fine-tuning Author contributions: K.K., H.A., and K.M. designed research; K.K., J.W., M.Y., S.T., S.N., IMMUNOLOGY mechanism using paired receptors families in which members A.K., T.S., and K.M. performed research; K.K., J.W., T.O., M.Y., N.M., M.K., H.A., and K.M. show opposite (activating and inhibitory) signaling even though analyzed data; and K.K., J.W., T.O., M.Y., N.M., H.A., and K.M. wrote the paper. their cognate ligand recognitions are essentially similar. It is be- The authors declare no conflict of interest. lieved that activating members exhibit lower affinity to ligands This article is a PNAS Direct Submission. than inhibitory members, possibly preventing undesired over- Data deposition: Crystallography, atomic coordinates, and structure factors reported in activation of immune responses (2–4) [e.g., killer cell Ig-like this paper have been deposited in the Protein Data Bank, www.pdb.org (PDB ID code receptors, CD94/NKG2 heterodimers, leukocyte Ig-like receptors, 3WUZ and 3WV0). 1 and CD28/CTLA-4 (5)]. Paired Ig-like type 2 receptor (PILR) is K.K., J.W., T.O., M.Y., and S.T. contributed equally to this work. a member of a paired receptor family comprising activating and 2Present address: Department of Physiology and Pharmacology, University of Calgary, inhibitory members designated “PILRβ” and “PILRα,” respec- Calgary, AB, Canada T2N 4N1. 3 tively. PILRs have one Ig-like domain in the extracellular region, Present address: Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto 606-8397, Japan. which is responsible for the ligand recognition. Our previous 4 O Present address: Institut National de la Santé et de la Recherche Médicale U932, Institut reports showed that PILRs recognize the -glycosylated mucin Curie, 75005 Paris, France. proteins, mouse CD99 (6), and PILR-associating neural protein 5To whom correspondence may be addressed. E-mail: [email protected] or (PANP) (7). A recent study identified two O-glycosylated ligands [email protected]. for PILRs, neuronal differentiation and proliferation factor-1 This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. (NPDC1) and collectin-12 (COLEC12), expanding the PILR- 1073/pnas.1324105111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1324105111 PNAS | June 17, 2014 | vol. 111 | no. 24 | 8877–8882 Downloaded by guest on September 24, 2021 CD99 is broadly expressed on myeloid lineage cells, and it is α2–3 linkage did not. These findings suggest that the PILRα binds believed that PILR recognition of CD99 regulates the immune to a complex structure involving both sTn and peptides. response. Interestingly, activating PILRβ exhibits lower affinity for CD99 than inhibitory PILRα (11), likely to prevent over- activation of immune responses as suggested above. Similarly to CD99, COLEC12 is expressed on monocytes and vascular A sTn-T TF sTn-T(GPA)PAP endothelial cells, likely involving the immune system. PILRs also bind to PANP and NPDC1, both of which are expressed on neural tissues, enabling PILR-expressing cells either to stimulate or to inhibit their function; this binding indicates that PILRs have a role in neural tissues. On the other hand, paired receptor families often are targets for recognition by microorganism proteins or products that con- tribute to infection or to the suppression of the immune system Fluorescence intensity (4), e.g., Ly49H for m157 of murine CMV (12), LILRB1 for human CMV UL18 (13), unknown ligands of Staphylococcus B Sialic acid (Neu5A) aureus (14), and KIR3DL2 for CpG DNA of bacteria (15), among 2 others. We recently found that human PILRα is an entry receptor 6 for an essential unit, glycoprotein B (gB) of HSV-1 (16, 17). GalNAc α 1 Human PILR is an inhibitory receptor, and thus its binding to C HSV-1 gB could induce immune suppression and subsequently Gly-Pro-Ala-Thr-Pro-Ala-Pro promote HSV-1 immune evasion, even though gB cannot bind N 50 53 56 to PILRβ at a level that is detectable in infection assays (17). (-3) (+1) (+4) PILRs can bind to above-mentioned O-glycosylated proteins, expanding PILR ligand family members. In recognizing O-glycan, C PILR exhibits three unique characteristics: (i) the requirement for sialylation; (ii) core-1 structure specificity; and (iii) dependency on the peptide sequence attached to O-glycan (8, 18). Here we report that human PILRα recognizes both the sialylated O-linked sugar T antigen (sTn) and its attached peptide region (representa- tively selected from HSV-1 gB). Furthermore, we show that +sTn-T(GPA)PAP the O-glycosylated sTn peptide can be used to inhibit PILRα- mediated immune regulation and HSV-1 fusion. Furthermore, we have determined the crystal structures of both the free and complex (attached to the sTn peptide) forms of PILRα.The structures clearly reveal a previously unidentified mode of sugar–peptide–protein interaction that is dependent on both the O-linked sugar and, uniquely, on the peptide, thus simul- O taneously recognizing both the -liked sugar and its attached D peptide. Taken together, these results provide functional and hPILR sTn-T(GPA)PAP structural insights on recognition modes to O-glycosylated mucin family including sTn modifications (well-known cancer targets), which are important in immune system as well as HSV-1 entry mechanism. Results sTn O-Glycosylated Peptide Is an Essential Unit for PILRα Recognition.
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