Upload
phungmien
View
219
Download
0
Embed Size (px)
Citation preview
Supplementary Material
The glycobiology of the CD system: a dictionary for translating marker designa-
tions into glycan/lectin structure and function
Hans-Joachim Gabius1, Herbert Kaltner1, Jürgen Kopitz2, and Sabine André1
1Institute of Physiological Chemistry, Faculty of Veterinary Medicine, Ludwig-
Maximilians-Universität München, Veterinärstr. 13, 80539 Munich, Germany2Institute of Pathology, Department of Applied Tumor Biology, Ruprecht-Karls-Univer-
sität Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany
Tel. +49-(0)89-2180 2290
FAX: +49-(0)89-2180 992290
e-mail: [email protected] or [email protected]
CD11
This integrin subunit (M) is structurally composed of three sections (Figure 2): the in-
serted (I) domain (a module prominently acting in contact building to extracellular ma-
trix glycoproteins, the intercellular adhesion molecules (ICAMs)-1/-2, fibrinogen, the
platelet glycoprotein GPIb or the opsonic complement component inactivated (i)C3b),
a region binding divalent cations and the lectin-like domain (proximal to the membrane)
specific for -N-acetylglucosamine residues presented by N-glycans or for -glucans
[S1]. In complex with CD18 (2-integrin), CD11b forms the leukocyte complement recep-
tor 3 (or Mac-1 antigen). Engagement of its lectin activity lets the integrin become a sen -
sor for iC3b-coated cells and an effector for platelet clearance. Among its binding part-
ners, also called counter-receptors, is CD23.
CD23
This type II transmembrane glycoprotein of about 45 kDa with a C-type CRD is a low-
affinity IgE receptor (FcRII). Lectin activity is attributed to this CRD, and the localization
of its gene in a cluster with other sequences of C-type lectins such as CD209 (please see
below) indicates its origin by gene divergence [S2, S3]. Extracellularly, the CRD is con-
nected with a stalk region for oligomerization so that the distal lectin sites can form
clusters (Figure 2). Key interaction partners are IgE, CD21 and CD11b/CD18. Capacity
for signaling leading to pro-inflammatory cytokine responses allows cell surface-pre-
1
sented and soluble (after ADAM10-dependent cleavage) CD23 to be classified as an im-
mune regulator.
CD31
The platelet endothelial cell adhesion molecule-1 (PECAM-1) belongs to the Ig superfa-
mily with its six extracellular C2-type domains. These versatile modules afford the struc-
tural basis for homophilic and also for heterophilic interactions with proteins such as
CD38 (ADP-ribosyl cyclase). The C2-type domains are followed by the transmembrane
section and the cytoplasmic tail (118 amino acids) [S4, S5]. That each domain has dis-
tinct features broadens the spectrum of in situ binding partners to include glycosamino-
glycans. In detail, whereas homophilic events critically depend on Ig-like domain 1, high-
affinity binding sites for heparin/heparan sulfate are located in Ig-like domains 2 and 3
[S6].
CD44
This rather ubiquitous type I transmembrane glycoprotein is known for its occurrence
in a wide variety of isoforms through alternative splicing. A single link module at the N-
terminus (residues 32-124), also called a link protein homology region, conveys binding
capacity to hyaluronic acid to CD44 isoforms, as it does for the hyaladherins LYVE-1 and
the product of tumor necrosis factor--stimulated gene-6 (TSG-6), for the hyaluronan
receptor for endocytosis (HARE) and the extracellular matrix glycoproteins aggrecan,
brevican, neurocan and versican, which are also known as lecticans due to the presence
of a C-type CRD [S7, S8].
CD56
The neural cell adhesion molecule-1 (NCAM-1), another member of the Ig superfamily, is
encoded by a single gene and, like CD44, present in many (up to 30) isoforms due to en-
suing processing. The molecular weights and mode of membrane anchoring can differ
among isoforms. Its extracellular region is composed of five Ig-like C2-type domains
(two stacked -sheets cross-linked by a disulfide bond) and two fibronectin type III-like
modules, which are proximal to the membrane [S9, S10]. Typical features of its N-
glycosylation are the presence of 2,8-linked polysialic acid, oligomannosidic structures
and the HNK-1 epitope (CD57, Figure 1) [S9, S10]. As noted for CD31, individual Ig-like
modules have acquired particular binding properties: the fourth Ig-like domain can ac-
2
commodate oligomannosidic glycans, and the second module binds heparan sulfates
[S11].
CD62E,L,P
That lymphocytes from distinct lymphoid sites were able to find their way back to their
original home after re-injection into animals was interpreted as evidence for tissue-spe-
cific adhesion mechanisms [S12]. As outlined in the introductory section, monoclonal
antibodies against three different cell surface glycoproteins were crucial for the identifi-
cation of the protein side of the assumed recognition. The three selectins, present in en-
dothelial (E) cells, lymphocytes (L) or platelets (P), share the modular display with the
N-terminal C-type CRD followed by an epidermal growth factor (EGF)-like domain, two
(CD62L) to nine (CD62P) short consensus repeats known from complement-regulatory
proteins (also called sushi domain), then completed by the about 25-amino-acid-long
transmembrane section and the C-terminal cytoplasmic tail (Figure 2) [S13].
Summarizing this domain composition, the descriptive term LEC-CAM (Lectin-Egf-Com-
plement Cell Adhesion Molecule) had been used synonymously. CD15s (Figure 1) is
among the pan-selectin binders; the glycan-lectin association is driven by the entropic
gain (TS: 23 kJ mol-1) [S14, S15]. Preformed complementarity between the contact sur-
faces leading to directional polar interactions accounts for a fast on-rate (>106 M-1s-1) in
selectin binding, which is essential to allow anchoring of cells flowing by in the blood
[S16]. Tyrosine sulfation can serve as non-glycan part of the docking site, e.g. in P-se-
lectin glycoprotein ligand-1 (PSGL-1) (Tys7/Tys10) [S16] or the glycoprotein T cell
immunoglobulin and mucin domain 1 (TIM-1) [S17]. Of interest, TIM-1 recognition by
CD62E,P is operative without sialylation, which is a key determinant in binding PSGL-1
or CD44 [S17]. In addition to acting as a natural braking system to slow down leukocytes
on an endothelial surface, the selectin (CD62)-counterreceptor recognition underlies the
phenomenon of rolling of cells by formation of catch bonds. Their lifetime increases un-
der shear stress, likely involving re-orientation of the C-type CRD against the EGF-like
domain [S18]. The selectin-dependent phase is the prerequisite for the transition from
rolling to firm adhesion mediated by integrins.
3
CD94
This antigen is expressed on NK cells. Activating receptors can make NK cells prone to
also attack self targets, leading to auto-aggression. In order to counterbalance respective
signaling, inhibitory mechanisms have developed based on three receptor classes.
Among MHC class I receptors, the C-type lectin CD94 becomes disulfide bridged to a sig-
naling companion of the NKG2 family, building a heterodimer (Figure 2). NKG2 genes,
coding for type II transmembrane proteins with an extracellular C-type lectin-like do-
main, belong to the NK complex on the short arm of human chromosome 12 [S19, S20].
Having first (expectedly) been detected by monoclonal antibodies [S21], CD94 is now
that the presence of the CRD is known referred to as another member of the family of C-
type lectins. Its own cytoplasmic portion is restricted in length to only seven amino acids
[S22]. Consequently, CD94 makes use of the signaling motif of the NKG2 protein (A, B, C,
E or H). Association with NKG2A/B brings their consensus ITIM (Immunoreceptor Tyro-
sine-based Inhibitory Motif) sequence into the complex, engendering the negative effect
on NK cell activity (please see CD170 and CD328 for the role of ITIMs in siglecs). Attest-
ing to its physiological role, antibody blocking of CD94 reduced NK cell-mediated cyto-
toxicity against human melanoma cells with a high-level sialyl Lex (CD15s) presentation,
as did a neoglycoconjugate with this epitope (inert carrier with custom-made chemical
glycosylation as bioactive part [S23]). These experiments provided first information of
CD94’s lectin activity [S24]. Tri- and tetraantennary N-glycans with 2,3-sialylation (of
the human 1-acid glycoprotein) and heparin (conjugated to bovine serum albumin)
were later described to bind to a fusion protein with the C-type lectin CRD of CD94 as
sensor, as they did to similarly engineered NKG2D [S25, S26].
CD141
Thrombomodulin is a predominantly endothelial glycoprotein that has anticoagulant
activity, through inhibition of the pro-coagulant thrombin and by serving as cofactor for
thrombin-catalyzed activation of the anti-coagulant protein C [S27]. It controls multiple
biological processes in inflammation and vascular integrity, therefore looking at its
modular design is a step toward unraveling structure-activity relationships: following a
short cytoplasmic tail and the transmembrane region, the extracellular portion com-
prises a serine/threonine-rich section with a chondroitin sulfate chain (relevant for an-
ticoagulation; for further information on glycosaminoglycans/proteoglycans, please see
[S7, S28]), six EGF-like repeats, a hydrophobic region and the C-type CRD (Figure 2). The
4
lectin module is a receptor for Ley determinants (CD174, Figure 1) on lipopolysaccha-
ride, connected to CD141’s activity to confine tissue damage, and on cellular glycopro-
teins such as the EGF receptor, to block its angiogenic activity [S29, S30].
CD169
This 185-kDa member of the Ig-like family (a type I transmembrane glycoprotein with
its CRD in the distal V-set Ig-like domain followed by 16 extracellular C2-type modules
to give the CRD excellent spatial accessibility, Figure 2) was the first Ig-like receptor
found to have binding specificity for sialylated glycans. It was thus termed siglec (sialic
acid-binding Ig-like lectin). Its original name ‘sheep erythrocyte receptor’ was based on
results of experiments studying adhesion activities on resident bone marrow macro-
phages, whose association to unopsonized erythrocytes was reduced by 3’-sialyllactose
and ganglioside GD1a [S31]. The SER-4 blocking antibody, raised against murine serum-
induced peritoneal macrophages, was applied in affinity chromatography. This method
facilitated the purification of the lectin (now named sialoadhesin or siglec-1), which is
known to be a marker for macrophages in transition regions. Siglec-1 has affinity to
2,3-sialylated Thomsen-Friedenreich (TF) disaccharide (CD176s) in sialoglycoproteins
(human glycophorin) and to the glycan chains of certain gangliosides (GT1b, GD1a and
GM3) [S32]. The exceptionally length of its extracellular section (17 Ig-like domains
compared to two to seven in other siglecs) makes it ideally suited for trans-interactions.
A preferential role of siglec-1 as an active player in mediating interactions with other
cells is further supported by the absence of an intracellular ITIM or any other tyrosine-
harboring putative signaling motif. Siglec-1 can bridge lymphocytes/tumor cells and
macrophages, via recognition of sialomucins leukosialin (CD43) on T cells or MUC-1 on
breast cancer cells, as glycans of the siglec, in addition, become sites for associating cells
by a C-type macrophage lectin (CD301) or by CD206. Of note, surface epitopes of human
pathogens, i.e. sialylated lipooligosaccharides from Campylobacter jejuni and Neisseria
meningitidis, are targets of siglec-1 in host defence [S33, S34] (for information on bacte-
rial glycosylation, please see [S35]). On the chromosomal level, the genes for human and
murine siglec-1 are not part of the gene cluster for the reminder of the siglec family on
human chromosome 19q or mouse chromosome 7 but located on chromosomes 20
(human) or 2 (mouse) [S36].
5
CD170
Siglec-5 was the first member of this lectin family to be tracked down by a computa-
tional homology search, using the CD33 (siglec-3) sequence and a database containing
more than one million expressed sequence tags [S37]. It contains one V-set and three
C2-set Ig-like domains that have specificity toward sialic acid irrespective of its linkage
to the rest of the glycan. As for all eight human CD33-related siglecs, CD170 has a mem-
brane-proximal ITIM sequence and a distal ITIM-like motif in its cytoplasmic tail. Tyro-
sine phosphorylation recruits the protein-tyrosine phosphatases SHP-1/-2 (two Src ho-
mology (SH)-1/-2 domain-containing enzymes) for inhibitory signaling [S38]. Despite its
initial classification as OB-BP2 (binding protein for the product of the putative obesity
gene, which codes for leptin, causing extreme obesity) its low level of reactivity was con-
sidered “unlikely to be physiologically relevant” [S39]. Expression was detected in
granulocytes and B lymphocytes, its paired activating receptor siglec-14, a product of
concerted evolution, is present on monocytes instead of B cells, illustrating that there
can be unique features even between very closely related family members [S40]. Special
among siglecs, it is engaged in a protein-dependent (sialic acid-independent) interaction
with the cell wall-anchored -protein of group B Streptococcus, which subverts the ITIM-
based signaling of siglec-5 to dampen innate defense reactions [S41].
CD206
The macrophage (tandem-repeat-type) mannose receptor was first detected as endo-
cytic entry site for glycoproteins with mannose/N-acetylglucosamine-terminated N-gly-
cans on rat Kupffer cells [S42] (for further information on N-glycosylation, please see
[S9, S43]), later targeted with clinical benefit in enzyme replacement therapy [S44]. Its
modular design as type I transmembrane glycoprotein is composed of a cysteine-rich (-
trefoil) domain, a fibronectin type II module with collagen (I-IV) reactivity, eight C-type
lectin/lectin-like domains and the cytoplasmic tail with signals for delivery to and recy-
cling from early endosomes (Figure 2) [S45, S46]. As lectin, CD206 is thus bifunctional
via two structurally different sites: CRD no. 4 binds mannose, N-acetylglucosamine and
fucose, the segment of domains 4-8 is reactive with multivalent sugar ligands, and the -
trefoil domain has affinity for SO4-4-GalNAc1,4GlcNAc termini of N-glycans of glyco-
protein hormones [S47]. This capacity for glycan binding through two structurally dis-
tinct sites is unique within the group of the four mammalian endocytic receptors of this
type (not shared by the M-type phospholipase A2 receptor, urokinase-type plasminogen
6
activator receptor-associated protein Endo180 (CD280; discussed later) and the den-
dritic cell receptor DEC205 (CD205)). To give examples of glycan ligands, cell-specific
glycoforms of CD45 and CD169 are reactive with the -trefoil domain. As ligand for a
lectin, glycans of CD206 appear to associate with CD62L so that contact of lymphocytes
and lymphatic endothelium is mediated. Hereby, a role in immune cell trafficking is
added to the lectin’s activity for efficient glycoprotein endocytosis, with participation
also in antigen presentation [S48, S49].
CD207
Langerin is so named because the detecting monoclonal antibody (DCGM4) selectively
stained (via this 40 kDa antigen) Langerhans cells, a subset of dendritic cells residing in
skin epidermis and mucosal epithelium, [S50]. Like CD206, albeit type II, it is a glycopro-
tein that is active as endocytic receptor, but it has only one C-type CRD, not a tandem-
repeat display (Figure 2). Binding to oligovalent ligands is made possible by an ex-
tracellular neck region for trimerization stabilized by a coiled-coil of -helices as in
CD23. Uniquely for a C-type lectin with the mannose-binding tripeptide motif (Glu-Pro-
Asn), its CRD can also accommodate 6-sulfated galactose (e.g. the terminal sugar in the
glycosaminoglycan keratan sulfate) [S51]. Single nucleotide polymorphisms in the CRD
(K313I, N288D) act as an off switch for this specificity, a case of a direct effect of single-
site mutations on glycan binding [S52]. Alternatively, long-range consequences of such
sequence alterations are known to occur, e.g. in a lectin of a different family [S53]. In
addition, Ca2+-independent binding of heparan-sulfate-type glycosaminoglycans at the
trimeric neck region (involving Arg187) has been reported [S54]. Its endocytic capacity,
relevant for formation of Birbeck granules typical for Langerhans cells, and its reactivity
to fungal surfaces resemble the activity profile of related C-type lectins on dendritic cells
and macrophages. Thus, a group of cooperating C-type lectins, to which the next lectin
discussed (CD209) belongs, have distinct glycan-binding features to cover a broad range
of pathogenic glycan signatures [S55, S56].
CD209
The genes for this dendritic C-type lectin and the closely related liver/lymph node-spe-
cific CD209L/CD299 (also called DC-SIGNR- or L-SIGN; please see below) are part of a
cluster on chromosome 19p13.3, along with the gene for CD23 [S57]. It was originally
detected as contact partner for the glycoprotein gp120 of the human immunodeficiency
7
virus by expression cloning using a placental cDNA library [S58]. Later, it was shown to
connect resting T cells that present ICAM-3 to dendritic cells, explaining its name as
dendritic cell-specific ICAM-3-grabbing non-integrin (DC-SIGN) [S59]. The 44 kDa glyco-
protein is a type II transmembrane receptor with a 40-amino-acid intracellular section
harboring at least three intracellular sorting motifs, a neck for tetramer formation and
the C-type CRD (Figure 2). The CRD has affinity for mannose and for Le epitopes (similar
to CD207), the further affinity for Ley (CD174) shared by CD141 [S60, S61]. The lectin is
found in immature (periphery) and mature (lymphoid sites) dendritic cells (but not
plasmacytoid/follicular dendritic cells) and macrophages (M2, CD14+). In addition to
roles in cell adhesion and antigen presentation, DC-SIGN helps shape immune responses
as the pathogen sensor of a signalosome (containing the three scaffold proteins LPS-1,
KSR-1 and DNK and the kinase Raf-1) [S62] (for comment on relevance of elucidating in
vivo functions in murine knock-out models, please see section on CD299). Acting as
docking site for viral glycans, CD209 counterintuitively promotes infection (as similarly
seen for CD169, CD206, CD294, CD301-303: for recent review, please see [S63]), a clini-
cally relevant lesson in how a defence line can be exploited by viral glycosylation.
CD222
The Ca2+-independent lectin property of this 300 kDa dimeric type I transmembrane
glycoprotein is assigned to a domain that is reactive with mannose-6-phosphate, thus it
is referred to as P-type CRD. The unusual ability to bind phosphomannosyl residues,
which is shared only by a second (cation-dependent) lectin, was delineated from studies
on fibroblasts of patients with the lysosomal storage disorder mucolipidosis-II (I-cell
disease), together with the discovery that this type of sugar is a marker (routing signal)
for lysosomal enzymes [S64]. Sequence alignments later uncovered homologies to three
proteins in the endoplasmic reticulum (erlectin (XTP3-B), OS-9 (upregulated in
osteosarcomas) and the 55 kDa non-catalytic -subunit of -glucosidase-II) as well as
the -subunit of the Golgi GlcNAc-phosphotransferase. As consequence, the P-type CRD
is now a part of the mannose-6-phosphate receptor homology (MRH) family. This CRD
present in two P-type lectins is responsible for uptake of cognate glycoproteins and their
intracellular trafficking [S65]. Similar to CD206, its extracellular domains, here a total of
15, are arranged in a tandem-repeat orientation (Figure 2). Carbohydrate binding was
localized to two high-affinity sites at domains 3 and 9 [S64]. Of note, domain 11 interacts
with insulin-like growth factor type 2 (IGF-2) [S64]. Thus, the receptor exhibits a dual
8
functionality to bind sugar and protein at different domains, and is thus referred to as P-
type lectin/IGF-2 receptor. Also, plasminogen, the precursor of the central enzyme of
fibrinolysis, interacts with domain 1, of potential relevance for its conversion to the
active serine protease plasmin, and retinoic acid is also a non-glycan binding partner
[S64]. Obviously, the P-type domain is subject to diversification with respect to
molecular interactions beyond sugars, as seen above for C- and I-type lectins. Three
separate internalization sequences guide the lectin’s intracellular routing. Loss of
heterozygosity at the locus of this gene occurs in human cancer, pointing to a role of a
deficiency in this receptor for enhancement of tumorigenicity in established tumor cells
[S66].
CD280
The quest to identify new members of the C-type lectin family led Wu et al. [S67] to
search the expressed sequence tag cDNA data base for homologues of the sequence mo-
tif for the CRD of CD62E. Although the sequence hit only reached a degree of “low ho-
mology (~ 23 %)” in total, it had the same amino acids at positions that are conserved
among C-type lectins, and cloning yielded a sequence with a remarkable degree of iden-
tity (32.5-34%) to the known members of the mannose receptor (CD206) family [S67].
Independently, CD280, at that time referred to as glycoprotein (p180), had been de-
scribed as constitutively recycling surface antigen (Endo180) in human fibroblasts [S68]
and as urokinase plasminogen activator receptor-associated protein (uPARAP) [S69].
Similar to CD206, Endo180 is also a collagen receptor via its fibronectin type II region; in
contrast to CD206, the cysteine-rich domain is not a lectin. Besides the common protein-
collagen contact, the second C-type lectin domain of this receptor is also capable of in-
teracting with O-glycosylated collagen, which CD206 cannot do [S70]. The nearly com-
plete abrogation of collagen endocytosis, diminished initial adhesion to collagens and
impaired migration of murine fibroblasts deficient in this receptor intimate CD280’s
importance for cellular collagen interactions [S71].
9
CD299
The sinusoidal endothelial cell receptor DC-SIGNR (L-SIGN, CD209L) shares its modular
display with the dendritic cell DC-SIGN (CD209), with 77 % amino acid sequence iden-
tity (Figure 2). Two features, besides the cellular expression profile, appear different by
comparison: i) Val351 in DC-SIGN, which creates a hydrophobic pocket for accommo-
dating 1,3/4-fucosylated Le epitopes and building van der Waals contacts with the 2’-
OH group of fucose, is substituted by Ser363 in CD299, making the interaction impossi-
ble in CD299 [S72] and ii) minor sequence variations in the neck domain for
tetramerization, which has 23-amino-acid repeats, account for the significantly en-
hanced stability of CD299 aggregates compared to CD209 tetramers [S73]. In gauging
the potential of mouse models to illuminate the physiological significance of these C-
type lectins, the occurrence of a recent, independent divergence of the murine gene
family leading to a total of seven expressed genes and a pseudogene, six proteins proven
to be lectins, is worth noting [S74].
CD328
Three separate approaches all converged to the identification, cloning and characteriza-
tion of expression of this CD marker: immunization of mice with human NK cell clones,
resulting in an antibody specific for adhesion inhibitory receptor molecule-1
(AIRM1/p75), screening of a human primary dendritic cell cDNA library for clones with
sequence similarity with the CD33 (siglec-3) gene and homology searches in the dbEST
division of the GenBank database [S75-77]. The structure of CD328 is composed of one
V-set and two C2-set Ig-like modules, which led to its classificiation as siglec-7, and
common inhibitory signaling motifs (Figure 2). It is related to siglec-5 (CD170) and iden-
tical in modular design to siglecs-6, 8, and 9, produced by NK, dendritic and CD8+ T cell,
respectively. Ligand engagement (including 2,8-linked sialosides) negatively impacts
NK cell cytotoxicity, as shown in response to recognition of ganglioside GD3 and the
disialosyl globopentaosylceramide DSGb5 [S78].
CD335/CD337
The natural cytotoxicity receptors NKp46 (CD335) and NKp30 (CD337) are glycopro-
teins with two C2-set (CD335) or one V-set (CD337) Ig-like domain(s) (Figure 2). They
exert their trigger capacity via association with signaling proteins that have immunore-
ceptor tyrosine-based activating motifs (ITAMs), mirroring how CD94 teams up with
10
ITIM-containing proteins to dampen NK cell responses [S79, S80]. Similar to CD94,
heparan sulfate-derived oligosaccharides are binding partners, as are N-glycans with
2,3-sialylation or sLex (CD15s) determinants [S81].
11
Table 1. CD-classified lectins (and lectin-like proteins) without PDB entry
Name Lectin class Modular design Expression Sugar specificity Function Ref.CD22(siglec-2)
I-type (siglec) One V-set and six C2-set Ig-like domainstransmembrane regionFour ITIM/ITIM-like sites, 1 growth factor receptor-bound protein 2 (Grb2)-binding motif
B cells Neu5Ac2,6Gal-[1,4GlcNAc(-6-sulfate)]
Negative regulator of B cell receptor signaling (inhibitory BCR coreceptor like CD72), also in response to binding complexes of antigen with soluble IgM, Grb2-dependent activation of alternative (positive) signaling
[S82, S83]
CD33(siglec-3)
I-type (siglec) One V-set and one C2-set Ig-like domainstransmembrane regionTwo ITIM/ITIM-like sites
Myeloid lineage incl. circulating monocytes, activated T/NK cells
Preference for Neu5Ac2,6Gal(1,4GlcNAc)mouse: sTn [CD175s]
Inhibitory signaling on cell activation/proliferation
[S84]
CD72(Lyb-2)
C-type (like) disulfide-linked homodimer with C-type lectin-like domain and leucine zippertransmembrane regionTwo ITIM/ITIM-like sites
B lineage cells(downregulated in plasma cells)
(CD5(?), CD100) Negative regulator of B cell receptor signaling (inhibitory BCR coreceptor, like CD22)
[S85]
CD83 I-type (siglec) One V-type Ig-like domaintransmembrane region40 amino-acid-
Mature dendritic cells
Sialic acid-dependent binding to monocyte glycoprotein (72kDa)
Assumed role in adhesion of dendritic cells to monocytes or subset of activated T cells
[S86]
12
long cytoplasmic tail
CD168[receptor for hyaluronic acid-mediated motility (RHAMM); IHABP: intracellular hyaluronic acid-binding protein]
Hyaladherin (without link domain)
C-terminal Bx7B motif in isoforms
Cell surface and intracellularly in many cell types (isoforms of 58-95 kDa)
Hyaluronic acid Motility during wound repair and cell growth
[S87]
CD205(DEC-205)
C-type (like) Cysteine-rich domain, fibronectin type II domain, ten C-type lectin/lectin-like domainstransmembrane regioncytoplasmic (31-amino-acid-long) tail
Dendritic cells, thymic cortical epithelium
?
(self) antigen uptake [S88]
CD301(MGL: macrophage galactose-type lectin)
C-type C-type CRD, neck domain for trimerizationtransmembrane regioncytoplasmic (29-amino-acid-long) tail with internalization signal
Dendritic cells, macrophages
(sialyl)Tn [CD175(s)]in mouse:CD301a: Lea,x
CD301b: Tn
Internalization/antigen presentation, pathogen/tumor pattern recognition, T cell recognition
[S89]
13
CD302[DEC-205/DEC-205-associated C-type Lectin-1 (DCL-1) fusion protein]
C-type (like) DEC-205 ectodomain and DCL-1 C-type lectin-like domaintransmembrane regioncytoplasmic (43-amino-acid-long) tail
Monocytes, macrophages, granulocytes, dendritic cells
?
Endocytosis/phagocytosis, adhesion of antigen-presenting cells
[S90]
CD303[blood DC antigen 2 (BDCA-2); LEC4C]
C-type (like) C-type lectin-like domain transmembrane regioncytoplasmic (21-amino-acid-long) tail
Peripheral dendritic cells, monocytes, macrophages, neutrophils
?
Antigen capture, antagonizes TLR signaling via Syk recruitment
[S91]
CD314(NKG2D)
C-type Disulfide-linked homodimer with C-type CRDtransmembrane regioncytoplasmic tail associating with DAP-10
NK cells, T cells, CD8+ T cells
2,3-sialylated N-glycans, heparin/heparan sulfate
NK cell activation receptor
[S92, S93, S94, S95, S96]
CD327 I-type (siglec) One V-set and two C2-set Ig-like domainstransmembrane regionTwo ITIM/ITIM-like sites
B cells, trophoblasts
Neu5Ac2,6GalNAc [sTn (CD175s)]
Negative regulator of trophoblast invasiveness in interplay with glycodelin-A
[S97]
14
CD329(siglec-9)
I-type (siglec) One V-set and two C2-set Ig-like domains transmembrane regionTwo ITIM/ITIM-like sites
Monocytes, neutrophils, subset of NK cells, immature dendritic cells
Neu5Ac2,3/6Gal1,4GlcNAc
Negative regulator of neutrophil growth and T cell receptor signaling, induces anti-inflammatory cytokines in macrophages
[S98]
CD330(siglec-10)
I-type (siglec) One V-set and fourC2-set Ig-like domainstransmembrane regionTwo ITIM/ITIM-like sites, one Grb2-binding motif
Eosinophils, monocytes, subset of NK cells, CD19+
B cells, CD4+ T cells
Neu5Ac2,3/6Gal1,4GlcNAc
Host protection by negative regulation of response to danger-associated molecular patterns (with CD24) or to activated T cells (with CD52)
[S99]
for information on CD69 (AIM: activation inducer molecule) /CD161 (KLRB1, NKR-P1A): reports on lectin activity have been corrected [S100, S101] or retracted [S102, S103]
15
References
S1 Hoffmeister, K.M. (2011) The role of lectins and glycans in platelet clearance. J. Thromb. Haemost. 9 Suppl 1, 35-43S2 Kijimoto-Ochiai, S. (2002) CD23 (the low-affinity IgE receptor) as a C-type lectin: a multidomain and multifunctional molecule. Cell. Mol. Life Sci. 59, 648-664S3 Acharya, M. et al. (2010) CD23/Fc RII: molecular multi-tasking. ε Clin. Exp. Immunol. 162, 12-23S4 Jackson, D.E. (2003) The unfolding tale of PECAM-1. FEBS Lett. 540, 7-14S5 Marelli-Berg, F.M. et al. (2013) An immunologist's guide to CD31 function in T-cells. J. Cell Sci. 126, 2343-2352S6 Gandhi, N.S. et al. (2008) Platelet endothelial cell adhesion molecule 1 (PECAM-1) and its interactions with glycosaminoglycans: 1. Molecular modeling studies. Biochemistry 47, 4851-4862S7 Buddecke, E. (2009) Proteoglycans. In The Sugar Code. Fundamentals of glycosciences (Gabius, H.-J., ed), pp. 199-216, Wiley-VCHS8 Misra, S., et al. (2011) Hyaluronan-CD44 interactions as potential targets for cancer therapy. FEBS J. 278, 1429-1443S9 Zuber, C. and Roth, J. (2009) N-Glycosylation. In The Sugar Code. Fundamentals of glycosciences (Gabius, H.-J., ed), pp. 87-110, Wiley-VCHS10 Ledeen, R.W. and Wu, G. (2009) Neurobiology meets glycosciences. In The Sugar Code. Fundamentals of glycosciences (Gabius, H.-J., ed), pp. 495-516, Wiley-VCHS11 Kleene, R. and Schachner, M. (2004) Glycans and neural cell interactions. Nat. Rev. Neurosci. 5, 195-208S12 Gowans, J.L. and Knight, E.J. (1964) The route of recirculation of lymphocytes in the rat. Proc. R. Soc. London Series B 159, 257-282S13 Vestweber, D. and Blanks, J.E. (1999) Mechanisms that regulate the function of the selectins and their ligands. Physiol. Rev. 79, 181-213S14 Magnani, J.L. (2004) The discovery, biology, and drug development of sialyl Lea and sialyl Lex. Arch. Biochem. Biophys. 426, 122-131S15 Binder, F.P. et al. (2012) Sialyl Lewisx: a "pre-organized water oligomer"? Angew. Chem. Int. Ed. 51, 7327-7331S16 Somers, W.S. et al. (2000) Insights into the molecular basis of leukocyte tethering and rolling revealed by structures of P- and E-selectin bound to sLex and PSGL-1. Cell 103, 467-479S17 Angiari, S. et al. (2014) TIM-1 glycoprotein binds the adhesion receptor P-selectin and mediates T cell trafficking during inflammation and autoimmunity. Immunity 40, 542-553S18 McEver, R.P. and Zhu, C. (2010) Rolling cell adhesion. Annu. Rev. Cell Dev. Biol. 26, 363-396S19 Houchins, J.P. et al. (1991) DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane proteins on human natural killer cells. J. Exp. Med. 173, 1017-1020S20 Yabe, T. et al. (1993) A multigene family on human chromosome 12 encodes natural killer-cell lectins. Immunogenetics 37, 455-460
16
S21 Aramburu, J. et al. (1990) A novel functional cell surface dimer (Kp43) expressed by natural killer cells and T cell receptor- /γ δ+ T lymphocytes. I. Inhibition of the IL-2-dependent proliferation by anti-Kp43 monoclonal antibody. J. Immunol. 144, 3238-3247S22 Lopez-Botet, M. et al. (1998) The CD94/NKG2 C-type lectin receptor complex. Curr. Top. Microbiol. Immunol. 230, 41-52S23 Chabre, Y.M. and Roy, R. (2009) The chemist’s way to prepare multivalency. In The Sugar Code. Fundamentals of glycosciences (Gabius, H.-J., ed), pp. 53-70, Wiley-VCHS24 Ohyama, C. et al. (2002) Natural killer cells attack tumor cells expressing high levels of sialyl Lewis x oligosaccharides. Proc. Natl. Acad. Sci. USA 99, 13789-13794S25 Imaizumi, Y. et al. (2009) NKG2D and CD94 bind to multimeric 2,3-linked N-αacetylneuraminic acid. Biochem. Biophys. Res. Commun. 382, 604-608S26 Higai, K. et al. (2009) NKG2D and CD94 bind to heparin and sulfate-containing polysaccharides. Biochem. Biophys. Res. Commun. 386, 709-714S27 Weiler, H. and Isermann, B.H. (2003) Thrombomodulin. J. Thromb. Haemost. 1, 1515-1524S28 Turnbull, J.E. (2015) Complexity and functional diversity of glycosaminoglycans: master cell regulators. Trends Biochem. Sci., in pressS29 Shi, C.S. et al. (2008) Lectin-like domain of thrombomodulin binds to its specific ligand Lewis Y antigen and neutralizes lipopolysaccharide-induced inflammatory response. Blood 112, 3661-3670S30 Kuo, C.H. et al. (2012) The recombinant lectin-like domain of thrombomodulin inhibits angiogenesis through interaction with Lewis Y antigen. Blood 119, 1302-1313S31 Crocker, P.R. and Gordon, S. (1986) Properties and distribution of a lectin-like hemagglutinin differentially expressed by murine stromal tissue macrophages. J. Exp. Med. 164, 1862-1875S32 Crocker, P.R. et al. (1991) Purification and properties of sialoadhesin, a sialic acid-binding receptor of murine tissue macrophages. EMBO J. 10, 1661-1669S33 Klaas, M. and Crocker, P.R. (2012) Sialoadhesin in recognition of self and non-self. Semin. Immunopathol. 34, 353-364S34 O'Neill, A.S. et al. (2013) Sialoadhesin: a macrophage-restricted marker of immunoregulation and inflammation. Immunology 138, 198-207S35 Tan, F.Y.Y., et al. (2015) Sugar coating: bacterial protein glycosylation and host-microbe interactions. Trends Biochem. Sci., in pressS36 Mucklow, S. et al. (1995) Sialoadhesin (Sn) maps to mouse chromosome 2 and human chromosome 20 and is not linked to the other members of the sialoadhesin family, CD22, MAG, and CD33. Genomics 28, 344-346S37 Cornish, A.L. et al. (1998) Characterization of siglec-5, a novel glycoprotein expressed on myeloid cells related to CD33. Blood 92, 2123-2132S38 Avril, T. et al. (2005) Siglec-5 (CD170) can mediate inhibitory signaling in the absence of immunoreceptor tyrosine-based inhibitory motif phosphorylation. J. Biol. Chem. 280, 19843-19851S39 Patel, N. et al. (1999) OB-BP1/Siglec-6: a leptin- and sialic acid-binding protein of the immunoglobulin superfamily. J. Biol. Chem. 274, 22729-22738S40 Yamanaka, M. et al. (2009) Deletion polymorphism of SIGLEC14 and its functional implications. Glycobiology 19, 841-846S41 Carlin, A.F. et al. (2009) Group B Streptococcus suppression of phagocyte functions by protein-mediated engagement of human Siglec-5. J. Exp. Med. 206, 1691-1699S42 Schlesinger, P.H. et al. (1978) Plasma clearance of glycoproteins with terminal mannose and N-acetylglucosamine by liver non-parenchymal cells. Studies with beta-
17
glucuronidase, N-acetyl- -D-glucosaminidase, ribonuclease B and agalacto-βorosomucoid. Biochem. J. 176, 103-109S43 Corfield, A. and Berry, M. (2015) Current aspects of eukaryotic glycosylation. Trends Biochem. Sci., in pressS44 Brady, R.O. (2006) Enzyme replacement for lysosomal diseases. Annu. Rev. Med. 57, 283-296S45 Taylor, P.R. et al. (2005) The mannose receptor: linking homeostasis and immunity through sugar recognition. Trends Immunol. 26, 104-110S46 Martinez-Pomares, L. (2012) The mannose receptor. J. Leukoc. Biol. 92, 1177-1186S47 Fiete, D. et al. (1997) The macrophage/endothelial cell mannose receptor cDNA encodes a protein that binds oligosaccharides terminating with SO4-4-GalNAc1,4GlcNAc or Man at independent sites. Proc. Natl. Acad. Sci. USA 94, 11256-11261S48 Martínez-Pomares, L. et al. (1999) Cell-specific glycoforms of sialoadhesin and CD45 are counterreceptors for the cysteine-rich domain of the mannose receptor. J. Biol. Chem. 274, 35211-35218S49 Marttila-Ichihara, F. et al. (2008) Macrophage mannose receptor on lymphatics controls cell trafficking. Blood 112, 64-72S50 Valladeau, J. et al. (1999) The monoclonal antibody DCGM4 recognizes Langerin, a protein specific of Langerhans cells, and is rapidly internalized from the cell surface. Eur. J. Immunol. 29, 2695-2704S51 Feinberg, H. et al. (2011) Structural basis for langerin recognition of diverse pathogen and mammalian glycans through a single binding site. J. Mol. Biol. 405, 1027-1039S52 Feinberg, H. et al. (2013) Common polymorphisms in human langerin change specificity for glycan ligands. J. Biol. Chem. 288, 36762-36771S53 Ruiz, F.M. et al. (2014) Natural single amino acid polymorphism (F19Y) in human galectin-8: detection of structural alterations and increased growth-regulatory activity on tumor cells. FEBS J. 281, 1446-1464S54 Chabrol, E. et al. (2012) Glycosaminoglycans are interactants of Langerin: comparison with gp120 highlights an unexpected calcium-independent binding mode. PLoS One 7, e50722S55 McGreal, E.P. et al. (2005) Ligand recognition by antigen-presenting cell C-type lectin receptors. Curr. Opin. Immunol. 17, 18-24S56 Lee, R.T. et al. (2011) Survey of immune-related, mannose/fucose-binding C-type lectin receptors reveals widely divergent sugar-binding specificities. Glycobiology 21, 512-520S57 Soilleux, E.J. et al. (2000) DC-SIGN, a related gene, DC-SIGNR, and CD23 form a cluster on 19p13. J. Immunol. 165, 2937-2942S58 Curtis, B.M. et al. (1992) Sequence and expression of a membrane-associated C-type lectin that exhibits CD4-independent binding of human immunodeficiency virus envelope glycoprotein gp120. Proc. Natl. Acad. Sci. USA 89, 8356-8360S59 Geijtenbeek, T.B. et al. (2000) Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell 100, 575-585S60 Gabius, H.-J. (2006) Cell surface glycans: the why and how of their functionality as biochemical signals in lectin-mediated information transfer. Crit. Rev. Immunol. 26, 43-79S61 Zhang, F. et al. (2014) DC-SIGN, DC-SIGNR and LSECtin: C-type lectins for infection. Int. Rev. Immunol. 33, 54-66
18
S62 Vautier, S. et al. (2012) C-type lectin receptors and cytokines in fungal immunity. Cytokine 58, 89-99S63 Van Breedam, W. et al. (2014) Bitter-sweet symphony: glycan-lectin interactions in virus biology. FEMS Microbiol. Rev. 38, 598-632S64 Dahms, N.M. and Hancock, M.K. (2002) P-type lectins. Biochim. Biophys. Acta 1572, 317-340S65 Castonguay, A.C. et al. (2011) Mannose 6-phosphate receptor homology (MRH) domain-containing lectins in the secretory pathway. Biochim. Biophys. Acta 1810, 815-826S66 Caixeiro, N.J. et al. (2013) Silencing the mannose 6-phosphate/IGF-II receptor differentially affects tumorigenic properties of normal breast epithelial cells. Int. J. Canc. 133, 2542-2550S67 Wu, K. et al. (1996) Characterization of a novel member of the macrophage mannose receptor type C lectin family. J. Biol. Chem. 271, 21323-21330S68 Isacke, C.M. et al. (1990) p180, a novel recycling transmembrane glycoprotein with restricted cell type expression. Mol. Cell. Biol. 10, 2606-2618S69 Behrendt, N. et al. (2000) A urokinase receptor-associated protein with specific collagen binding properties. J. Biol. Chem. 275, 1993-2002S70 Jurgensen, H.J. et al. (2011) A novel functional role of collagen glycosylation: interaction with the endocytic collagen receptor uparap/ENDO180. J. Biol. Chem. 286, 32736-32748S71 Engelholm, L.H. et al. (2003) uPARAP/Endo180 is essential for cellular uptake of collagen and promotes fibroblast collagen adhesion. J. Cell Biol. 160, 1009-1015S72 Guo, Y. et al. (2004) Structural basis for distinct ligand-binding and targeting properties of the receptors DC-SIGN and DC-SIGNR. Nat. Struct. Mol. Biol. 11, 591-598S73 Yu, Q.D. et al. (2009) Autonomous tetramerization domains in the glycan-binding receptors DC-SIGN and DC-SIGNR. J. Mol. Biol. 387, 1075-1080S74 Powlesland, A.S. et al. (2006) Widely divergent biochemical properties of the complete set of mouse DC-SIGN-related proteins. J. Biol. Chem. 281, 20440-20449S75 Falco, M. et al. (1999) Identification and molecular cloning of p75/AIRM1, a novel member of the sialoadhesin family that functions as an inhibitory receptor in human natural killer cells. J. Exp. Med. 190, 793-802S76 Nicoll, G. et al. (1999) Identification and characterization of a novel siglec, siglec-7, expressed by human natural killer cells and monocytes. J. Biol. Chem. 274, 34089-34095S77 Angata, T. and Varki, A. (2000) Siglec-7: a sialic acid-binding lectin of the immunoglobulin superfamily. Glycobiology 10, 431-438S78 Kawasaki, Y. et al. (2010) Ganglioside DSGb5, preferred ligand for Siglec-7, inhibits NK cell cytotoxicity against renal cell carcinoma cells. Glycobiology 20, 1373-1379S79 Moretta, L. et al. (2006) Surface NK receptors and their ligands on tumor cells. Semin. Immunol. 18, 151-158S80 Kruse, P.H. et al. (2014) Natural cytotoxicity receptors and their ligands. Immunol. Cell Biol. 92, 221-229S81 Ito, K. et al. (2011) Binding of natural cytotoxicity receptor NKp46 to sulfate- and
2,3-NeuAc-containing glycans and its mutagenesis. α Biochem. Biophys. Res. Commun. 406, 377-382S82 Schwartz-Albiez, R. et al. (1991) CD22 antigen: biosynthesis, glycosylation and surface expression of a B lymphocyte protein involved in B cell activation and adhesion. Int. Immunol. 3, 623-633S83 Nitschke, L. (2009) CD22 and Siglec-G: B-cell inhibitory receptors with distinct functions. Immunol. Rev. 230, 128-143
19
S84 Cao, H. and Crocker, P.R. (2011) Evolution of CD33-related siglecs: regulating host immune functions and escaping pathogen exploitation? Immunology 132, 18-26S85 Nitschke, L. and Tsubata, T. (2004) Molecular interactions regulate BCR signal inhibition by CD22 and CD72. Trends Immunol. 25, 543-550S86 Scholler, N. et al. (2001) CD83 is an I-type lectin adhesion receptor that binds monocytes and a subset of activated CD8+ T cells [corrected]. J. Immunol. 166, 3865-3872S87 Jiang, D. et al. (2011) Hyaluronan as an immune regulator in human diseases. Physiol. Rev. 91, 221-264S88 Shrimpton, R.E. et al. (2009) CD205 (DEC-205): a recognition receptor for apoptotic and necrotic self. Mol. Immunol. 46, 1229-1239S89 Mortezai, N. et al. (2013) Tumor-associated Neu5Ac-Tn and Neu5Gc-Tn antigens bind to C-type lectin CLEC10A (CD301, MGL). Glycobiology 23, 844-852S90 Kato, M. et al. (2007) The novel endocytic and phagocytic C-Type lectin receptor DCL-1/CD302 on macrophages is colocalized with F-actin, suggesting a role in cell adhesion and migration. J. Immunol. 179, 6052-6063S91 Geijtenbeek, T.B. and Gringhuis, S.I. (2009) Signalling through C-type lectin receptors: shaping immune responses. Nat. Rev. Immunol. 9, 465-479S92 Macher, B.A. et al. (1988) A novel carbohydrate, differentiation antigen on fucogangliosides of human myeloid cells recognized by monoclonal antibody VIM-2. J. Biol. Chem. 263, 10186-10191S93 Siebert, H.-C. et al. (2006) 2,3/2,6-Sialylation of N-glycans: non-synonymous signals with marked developmental regulation in bovine reproductive tracts. Biochimie 88, 399-410S94 Spitalnik, P.F. and Spitalnik, S.L. (1995) The P blood group system: biochemical, serological, and clinical aspects. Transfus. Med. Rev. 9, 110-122S95 Suchanowska, A. et al. (2012) A single point mutation in the gene encoding Gb3/CD77 synthase causes a rare inherited polyagglutination syndrome. J. Biol. Chem. 287, 38220-38230S96 Nudelman, E. et al. (1983) A glycolipid antigen associated with Burkitt lymphoma defined by a monoclonal antibody. Science 220, 509-511S97 Lam, K.K. et al. (2011) Glycodelin-A protein interacts with Siglec-6 protein to suppress trophoblast invasiveness by down-regulating extracellular signal-regulated kinase (ERK)/c-Jun signaling pathway. J. Biol. Chem. 286, 37118-37127S98 Cheong, K.A. et al. (2011) A novel function of Siglec-9 A391C polymorphism on T cell receptor signaling. Int. Arch. Allergy Immunol. 154, 111-118S99 Bandala-Sanchez, E. et al. (2013) T cell regulation mediated by interaction of soluble CD52 with the inhibitory receptor siglec-10. Nat. Immunol. 14, 741-748S100 Childs, R.A. et al. (1999) Recombinant soluble human CD69 dimer produced in Escherichia coli: reevaluation of saccharide binding. Biochem. Biophys. Res. Commun. 266, 19-23S101 Rozbesky, D. et al. (2014) Re-evaluation of binding properties of recombinant lymphocyte receptors NKR-P1A and CD69 to chemically synthesized glycans and peptides. Int. J. Mol. Sci. 15, 1271-1283S102 (2013) Retraction: Oligosaccharide ligands for NKR-P1 protein activate NK cells and cytotoxicity. Nature 500, 490S103 (2014) Retraction. Synthesis of LacdiNAc-terminated glycoconjugates by mutant galactosyltransferase – A way to new glycodrugs and materials. Glycobiology 24, 399
20