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ESSENTIALS OF GLYCOBIOLOGY LECTURE 22

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1 ESSENTIALS OF GLYCOBIOLOGY LECTURE 22
MAY 4, 2004 Richard D. Cummings, Ph.D. University of Oklahoma Health Sciences Center College of Medicine Oklahoma Center for Medical Glycobiology “THE C-TYPE LECTINS AND THE SELECTINS” Dr. Cummings

2 Historical Background Common Features of C-Type Lectins
Outline Historical Background Common Features of C-Type Lectins Localization and Functions of C-type Lectins The Endocytic Receptors The Collectins The Selectins The Natural Killer Lymphocyte Lectins Proteoglycans with C-type Lectin Domains Other Types of C-type Lectins Dr. Cummings

3 Historical Background
Prototypical Ca2+-dependent or C-type lectin: The Asialoglycoprotein Receptor (ASGPR) Work initiated by Gilbert Ashwell and Morell 1960s and 1970s 125I-labeled sialylated glycoprotein given i.v. into rabbits remained in serum with long half-life But the desialylated, 125I-labeled glycoprotein given i.v. was rapidly removed from circulation Removal of terminal galactose from 125I-labeled desialylated glycoproteins prolonged serum lifetime 125I-labeled desialylated glycoproteins sequestered in liver Ca2+-dependent receptor purified from rabbit liver membranes Two subunits, trimeric structure Other related proteins purified: trimeric structures with sequence similarities, but different carbohydrate binding specificity Name C-type lectin family proposed by Drickamer in 1988, based on similarities in sequence and Ca2+-dependency Dr. Cummings

4 -ENWGAGEPNNKKSKEDCVEIYIKRERDSGKWNDDACHKRKAALCY-
Common Features of C-type Lectins Conserved Carbohydrate-Recognition Domain of C-type Lectins LIVMFYATG FYWLIVSTA LIVMSTA DNSR WL —C— —X — —X— —X—X—C—X — — —C— n m n = 5 to 12 residues m = 5 to 12 residues Common Cystine-structure in C-type Lectins C C C C Rat Mannose Binding Protein C -ENWGAGEPNNKKSKEDCVEIYIKRERDSGKWNDDACHKRKAALCY- -TNWNEGEPNNVGSGENCVVLLT-----NGKWNDVPCSDSFLVVCE- Mouse L-selectin Dr. Cummings

5 Common Features of C-type Lectins
Dr. Cummings

6 Superfamily of Proteins Containing a C-type Lectin Domain (CTLD)
Common Features of C-type Lectins Superfamily of Proteins Containing a C-type Lectin Domain (CTLD) Members of this superfamily share a common primary and secondary structure that coordinates Ca2+. While all members of this superfamily of proteins have a CTLD, only about 1/2 of these members have a domain structure that promotes protein-carbohydrate interaction where the Ca2+is coordinated to the carbohydrate ligand. The remaining members may use the CTLD to bind other types of ligands, e.g. polypeptides, and thus promote protein-protein interaction, as for lecticans (proteoglycans with a CTLD). Dr. Cummings

7 Ca2+ Ca2+ from another CRD (From Feinberg et al, 2001)
Common Features of C-type Lectins Ca2+-Coordination by the CRD of DC-SIGN Ca2+ Ca2+ from another CRD 5 b2 4 a6 3 a3 b2 (From Feinberg et al, 2001) 1 2 Man GlcNAc Dr. Cummings

8 Left: Structure of the CRD of DC-SIGN bound to GlcNAc2Man3
Common Features of C-type Lectins Ca2+-Coordination by C-type Lectins Left: Structure of the CRD of DC-SIGN bound to GlcNAc2Man3 Right: Rat serum mannose-binding protein bound to a high-mannose oligosaccharide (From Feinberg et al, 2001) Dr. Cummings

9 Common Features of C-type Lectins
Crystal structure of a trimeric rat mannose-binding protein A (MBP-A) complexed with mannose at 1.8 Å resolution. Mannose is indicated in the stick figure and Ca2+ and Cl are indicated by the green and blue balls, respectively. Note that Ca2+ is closely coordinated with the bound sugar. (From Weis and Drickamer (1994) Structure 2: ) Dr. Cummings

10 Localization and Function of C-type Lectins
The CTLD is a versatile domain found within many proteins, including enzymes, proteoglycans, and adhesion molecules. C-type lectins are found as: Secreted Proteins and Glycoproteins Transmembrane Proteins and Glycoproteins (on both internal and plasma membranes) The CTLD in C-type Lectins function in: Cell-Cell Adhesion (e.g. Selectins) Glycoprotein Clearance by Endocytosis (e.g. ASGPR) Innate Immunity through Opsonizing Pathogens (e.g. Serum MBP) Innate Immunity through Endocytosis and Antigen Presentation (e.g. DC-SIGN) and Co-Regulation with Toll Receptors Dr. Cummings

11 Rat asialoglycoprotein receptor R2/3 (hepatic lectin 2/3)
Endocytic Receptors Rat asialoglycoprotein receptor R2/3 (hepatic lectin 2/3) Human asialoglycoprotein receptor (hepatic lectin H1) Chicken hepatic lectin Rat kupffer cell receptor Human macrophage mannose receptor Dendritic cell and thymic epithelial cells DEC-205 (homolog of macrophage mannose receptor) Murine macrophage asialoglycoprotein-binding protein (macrophage Gal/GalNAc-specific lectin - MMGL) Bovine 180 kD secretory phospholipase A2 receptor DEC 205 receptor Minkle (macrophage lectin inducible by TNF, IL-6 and INF-) DC-SIGN (Dendritic Cell-Specific ICAM-3 Grabbing Non-Integrin) the related DC-SIGN(R) appear to mediate interaction of T cells with dendritic cells via recognition of glycans on ICAM-3 Dr. Cummings

12 Endocytic Receptors Dr. Cummings

13 Endocytic Receptors (From Geijtenbeek et al (2004)Ann. Rev. Immunol. 22, 33-54) Dr. Cummings

14 Endocytic Receptors “ Recognition of pathogens such as mycobacteria by the CLR DC-SIGN and TLRs can lead to immune activation when the TLR-signal overrules that of the CLR, and this includes DC differentiation. This can occur when low amounts of pathogens target the CLR. When high concentrations of pathogens target the CLR DC-SIGN, the immune tolerizing signals can overrule the TLR-induced signals and inhibit DC differentiation, leading to immune suppression and pathogen survival.” (From Geijtenbeek et al (2004)Ann. Rev. Immunol. 22, 33-54) DC- SIGN Toll Receptor (TLR) Dr. Cummings

15 Human serum mannose-binding lectin (MBL)
Collectins Collectins (collagen-like sequences and lectin domains; function in innate immunity; fix complement in absence of antibody and have opsonin activity) Human serum mannose-binding lectin (MBL) Rat mannose binding protein A and C Human pulmonary surfactant-associated protein A (SP-A) Human pulmonary surfactant-associated protein D (SP-D) CL-L1 CL-P1 Conglutinin (bovine) CL-43 (bovine) CL-46 (bovine), Ficolins L-ficolin M-ficolin H-ficolin Human tetranectin (TN) (Plasminogen-kringle 4 binding protein) Dr. Cummings

16 Different Forms of Collectins
Dr. Cummings

17 Crystal Structures of Collectins
mannan-binding lectin (MBL) (with attached GlcNAc) Tachylectin from horseshoe crab (with attached GlcNAc) Larger fgb of tachylectin from horseshoe crab (with attached GlcNAc) From: Holmskov et al (2003) Ann. Rev. Immunol. 21, Dr. Cummings

18 Selectins Dr. Cummings

19 Similarities in C-type Lectin Domain Structure
Selectins Similarities in C-type Lectin Domain Structure of Selectins and Other CTLDs MBP-C E-Selectin P-Selectin Dr. Cummings

20 Selectins Dr. Cummings

21 Selectins Dr. Cummings

22 Selectins Dr. Cummings

23 Ser/Thr Selectins a3 a3 b4 a3 b3 a1 Gal GalNAc GlcNAc Fuc
Core 2-based SIALYL LEWIS X EPITPOPE (sLex) a3 b4 a3 b3 a1 Ser/Thr Gal GalNAc GlcNAc Fuc NeuAc S Sulfate Dr. Cummings

24 Selectins From: Leppanen et al (2003) J Biol Chem 278(29):26391-400
From: Somers et al (2000) Cell 103(3):467-79 Dr. Cummings

25 P-selectin Recognition of Fucose, Sialic, and Tyrosine Sulfate in
Selectins P-selectin Recognition of Fucose, Sialic, and Tyrosine Sulfate in Glycosulfopeptides From: Somers et al (2000) Cell 103(3):467-79 Dr. Cummings

26 Sulfated Glycans Recognized by L-selectin
Selectins Sulfated Glycans Recognized by L-selectin Ser/Thr a3 a1 b4 b3 6S 6-sulfo-sLex MECA-79 Gal Fuc GlcNAc GalNAc NeuAc S Sulfate From: Rosen (2004) Annu Rev Immunol. 22: Dr. Cummings

27 NK receptors (required for MHC-1 recognition)
The Natural Killer Lymphocyte Lectins Lymphocyte lectins NK receptors (required for MHC-1 recognition) (the CTLD functions in protein-protein interaction) Ly49A through W NKR-P1 CD94/NKG2A/B, -C or -E NKG2D CD69 human mast cell function associated antigen (MCFA) activation-induced C-type lectin (AICL) human eosinophil granule major basic protein human low affinity IgE Fc receptor (CD23) (ON LYMPHOCYTES AND MONOCYTES) P47 or LSLCL (lymphocytic secreted long form of C-type lectin) CIRE (expressed by splenic dendritic cells) Dr. Cummings

28 in Protein-Protein Interactions:
The Natural Killer Lymphocyte Lectins Importance of the CTLD in Protein-Protein Interactions: The NK Receptors Ly49A Ly49I Anatomy of C-type lectin-like domains of NK receptors. Ribbon diagrams of Ly49A, Ly49I (1JA3), NKG2D (1HQ8), CD69 (1FM5), CD94 (1B6E), and MBP-A. The secondary structural elements are colored as follows: b-strands blue, -helices red, and loop regions gold. The disulphide bonds are shown in green as ball-and-stick representation. The Ca2+ ions bound to MBP-A are drawn as magenta spheres. NKG2D CD69 MBP-A CD94 Dr. Cummings

29 in Protein-Protein Interactions:
Importance of the CTLD in Protein-Protein Interactions: The NK Receptors Recognition of MHC-I by the Ly49A, KIR2DL and NKG2D NK cell receptors. The KIR2DL2/HLA-Cw3 and NKG2D/MICA complexes (50, 58) were superimposed onto the Ly49A/H-2Dd complex using equivalent C atoms of the 1 and 2 domains of the MHC-I molecules. For clarity, the only MHC-I molecule shown is H-2Dd. The H-2Dd heavy chain is gold, the peptide is blue, and ß2m is gray. The Ly49A monomers interacting at Site 2 are cyan and light blue, KIR2DL is magenta, and the NKG2D monomers are green and pink. The overlapping area of KIR2DL and NKG2D is transparent. From: Natarajan K, Dimasi N, Wang J, Mariuzza RA, Margulies DH. (2002) Annu Rev Immunol 20:853-85 Dr. Cummings

30 rat brevican core protein (brain-enriched HA binding protein)
Proteoglycans with C-type Lectin Domains Proteoglycans human versican core protein (large fibroblasts proteoglycan - CS proteoglycan core protein-2 - glial hyaluronate binding protein) human aggregan core protein (cartilage-specific proteoglycan core protein - CSPCP- CS proteoglycan core protein-1) rat brevican core protein (brain-enriched HA binding protein) rat neurocan core protein (245 kD early post-natalcore glycoprotein) Other Types of C-type Lectins human integral membrane protein DGCR2/IDD human lithostathine 1 aprecursor (pancreatic stone protein - PSP) human polycystin human endothelial cell scavenger receptor human pancreatitis-associated protein 1 (PAP or HIP) human pancreatic beta cell growth factor (INGAP) Dr. Cummings

31 Lectin BRA-2 (coelomic fluid of acorn barnacle Megabalanus rosa)
Other Types of C-type Lectins Invetebrate Lectins Limulus clotting factor (hemolymph of horseshoe crab Tachypleus tridentatus) Lectin BRA-2 (coelomic fluid of acorn barnacle Megabalanus rosa) Newt Lectin (oviduct of iberian ribbed newt Pleurodeles waltii) Inducible Flesh fly lectin (Sarcophaga peregrina) Tunicate lectin (Polyandrocarpa misakiensis) Integral Spicule matrix lectin in sea urchin (Strongylocentrotus purpuratus) Sea urchin Echinoidin (Anthocidaris crassispina) Cockroach lectin (hemolymph of Periplaneta americana) Antifreeze protein (AFP) from the sea raven (Hemitripterus americanus) Viral Lectins Hepatic lectin homolog in Fowlpox virus gp22-24 in Vaccinia virus Dr. Cummings

32 Phospholipase A2 inhibitor subunit B (Trimeresurus flavoviridis)
Other Types of C-type Lectins Snakes and Venoms Alboaggregin A subunit 1 (white-lipped pit viper (Trimeresurus albolabris) Phospholipase A2 inhibitor subunit B (Trimeresurus flavoviridis) Echicetin alpha subunit (saw-scaled viper Echis carinatus) Coagulation factor IX/factor X-binding protein A (IX/X-BP) (Trimeresurus flavoviridis) Galactose-specific lectin (Crotalus atrox) Botrocetin, alpha chain (platelet coagglutinin) (Bothrops jararaca) Dr. Cummings


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