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ESSENTIALS OF GLYCOBIOLOGY LECTURE 22 MAY 7, 2002 Richard D. Cummings, Ph.D. University of Oklahoma Health Sciences Center College of Medicine Oklahoma.

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Presentation on theme: "ESSENTIALS OF GLYCOBIOLOGY LECTURE 22 MAY 7, 2002 Richard D. Cummings, Ph.D. University of Oklahoma Health Sciences Center College of Medicine Oklahoma."— Presentation transcript:

1 ESSENTIALS OF GLYCOBIOLOGY LECTURE 22 MAY 7, 2002 Richard D. Cummings, Ph.D. University of Oklahoma Health Sciences Center College of Medicine Oklahoma Center for Medical Glycobiology “THE C-TYPE LECTINS”

2 Prototype C-type lectin: Asialoglycoprotein receptor Ashwell and Morell 1960s and 1970s Rapid clearance of desialylated, radioactive glycoprotein after injection into circulation Removal of galactose prolonged serum lifetime Radioactive glycoproteins sequestered in liver Ca 2+ -dependent receptor purified from rabbit liver membranes –Two subunits, trimeric structure Other related proteins purified: trimeric structures with sequence similarities

3 -ENWGAGEPNNKKSKEDCVEIYIKRERDSGKWNDDACHKRKAALCY- -TNWNEGEPNNVGSGENCVVLLT-----NGKWNDVPCSDSFLVVCE- Mouse L-selectin Rat Mannose Binding Protein C -----------C---------------------------------C---------C-------C------- LIVMSTALIVMSTA FYWLIVSTAFYWLIVSTA —C— —X — —X— —X—X—C—X — —- —C— n = 5 to 12 residues DNSRDNSR WLWL LIVMFYATGLIVMFYATG n m m = 5 to 12 residues Conserved Carbohydrate-Recognition Domain of C-type Lectins

4 Selectins Plasma Membrane Endocytic Receptors Proteoglycans Collectins Lectin Domain EGF-Like Domain Complement Regulatory Repeat (Consensus Repeat) Fibronectin Type II Repeat OUT IN a N N N N N N N N C Variations in Structures of C-type Lectins

5 “Bouquet” Examples: Mannose-binding protein A Surfactant SP-A “Cruciform” Examples: Conglutinin Surfactant SP-D Variations in Structures of C-type Lectins

6 Endocytic receptors rat kupffer cell receptor human macrophage mannose receptor rat asialoglycoprotein receptor R2/3 (hepatic lectin 2/3) human asialoglycoprotein receptor (hepatic lectin H1) chicken hepatic lectin 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(R) appears to mediate interaction of T cells with dendritic cells via recognition of mannose containing glycans on ICAM-3[Geijtenbeek et al, 2000]. Types of C-type Lectins

7 Collectins (collagen-like sequences; function in innate immunity; fix complement and have opsonin activity) bovine collectin-43 bovine conglutinin rat mannose-binding protein A and C human mannose-binding protein human pulmonary surfactant-associated protein A (SP-A) human pulmonary surfactant-associated protein D (SP-D) human tetranectin (TN) (Plasminogen-kringle 4 binding protein) Types of C-type Lectins

8 Selectins L-selectin E-selectin P-selectin 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 immunoglobulin epsilon Fc receptor (CD23) P47 or LSLCL (lymphocytic secreted long form of C-type lectin) CIRE (expressed by splenic dendritic cells) Types of C-type Lectins

9 Others human integral membrane protein DGCR2/IDD human lithostathine 1  precursor (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) 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) Types of C-type Lectins

10 Invetebrate Lectins Limulus clotting factor (hemolymph of horseshoe crabTachypleus 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 Types of C-type Lectins

11 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) Types of C-type Lectins

12 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 Ca 2+ and Cl are indicated by the green and blue balls, respectively. Note that Ca 2+ is closely coordinated with the bound sugar.

13 Left: Structure of the CRD of DC-SIGN bound to GlcNAc 2 Man 3 Right: Rat serum mannose-binding protein bound to a high-mannose oligosaccharide (From Feinberg et al, 2001) Ca2+-Coordination by C-type Lectins

14 Interaction of the 1-3-linked branch with DC-SIGNR. For clarity, the remaining sugar residues are shown schematically. Ca2+ coordination bonds are shown as solid black lines; hydrogen bonds, as dashed lines. Large cyan sphere is Ca2+; red, oxygen; blue, nitrogen

15 Interactions of the 1-3-linked branch with DC-SIGN. The terminal GlcNAc1 forms a cross-link by forming the typical C-type lectin interactions with the principal Ca2+ site of another CRD. For clarity, only the coordination bonds to the Ca2+ (gray) are shown Ca2+-Coordination by C-type Lectins

16 C-type lectin-like domains (CTLDs) of higher eukaryotes are protein modules originally identified as carbohydrate-recognition domains (CRDs) in a family of Ca 2+ -dependent animal lectins. Less closely related but still definitely homologous CTLDs have been identified in a variety of proteins that do not appear to have carbohydrate-binding activity. All of the domains in the CTLD group show distinct evidence of sequence similarity and are thus believed to have descended from a common ancestor by a process of divergent evolution. (from Drickamer, K and Dodd, RB (1999) Glycobiology, 9, 1357-1369. Convergent Evolusion of C-type Lectin Domains (CTLDs)

17 (From Dodd RB, Drickamer K. (2001) Lectin-like proteins in model organisms: implications for evolution of carbohydrate-binding activity. Glycobiology 11(5):71R-9R) Types of C-type Lectins

18 I - Proteoglycans Aggrecan (major component of extracellular matrix of cartilagenous tissues. a major function of this protein is to resist compression in cartilage. it binds avidly to HA via an amino-terminal globular region.) Versican Neurocan Brevican Group I Proteoglycans Classification of C-type Lectins and Proteins with C-type Lectin Domains (CTLDs) Sushi Domain EGF Domain Link Region GAG Domain

19 II - Type 2 receptor IgE FcR (CD23) Asialoglycoprotein Receptor Subunit 1 Asialoglycoprotein Receptor Subunit 2 Macrophage Asialoglycoprotein Receptor Kupffer cell receptor DC immunoreceptor Scavenger receptor with CTLD Mincle Langerin DC-SIGN; DC-SIGNR Blood Dendritic Cell Antigen 2 (BDCA-2) Dendritic Lectin CLECSF11 HECL (CLECSF7) C-type lectin-like receptor CLEC-6 Group II Oligomeric Type 2 Receptors Classification of C-type Lectins and Proteins with C-type Lectin Domains (CTLDs)

20 III - Collectins Mannose-binding protein C Pulmonary Surfactant SP-A Mannose-binding protein A Pulmonary Surfactant SP-D Collectin-K1 Collectin-L1 IV - Selectins L-selectin E-Selectin P-selectin Group III Collectins Group IV Selectins Classification of C-type Lectins and Proteins with C-type Lectin Domains (CTLDs)

21 V - NK receptors Dectin-1 Mast cell function-associated antigen HNKR-P1A LLT1 CD69; CD69 homolog CD72 CD94 KLRF1 Oxidised LDL receptor CLEC-1 and -2 NKG2 A, C, D, E, H Myeloid DAP12-associating lectin (MDL-1) Group V Dimeric NK Cell Receptors Classification of C-type Lectins and Proteins with C-type Lectin Domains (CTLDs)

22 VI - MMR family Mannose Receptor Endo180 Phospholipase-A2 receptor DEC205 (GP200-MR6) Group VI Mannose Receptors Classification of C-type Lectins and Proteins with C-type Lectin Domains (CTLDs)

23 VII – Free CTLDs Lithostathine/Reg 1alpha Lithostathine/Reg 1beta Pancreatitis-associated protein/HIP Pancreatic beta cell Growth Factor Regenerating gene type IV VIII – Simple Type 1 receptors Layilin Layilin homolog Classification of C-type Lectins and Proteins with C-type Lectin Domains (CTLDs) Group VII Free CTLD

24 IX - Tetranectin  Tetranectin (plasminogen-binding protein)  Cartilage-derived CTL  Stem cell growth factor X - Polycystin  Polycystin Classification of C-type Lectins and Proteins with C-type Lectin Domains (CTLDs)

25 XI - Attractin  Attractin (rapidly and transiently expressed on the activated T lymphocyte that aids in the formation of clusters with monocytes & macrophages)  Attractin homolog XII - CTLD + acidic neck  KIAA0022 protein  Eosinophil Major Basic Protein (predominant constituent of the crystalline core of the eosinophil primary granule)  Eosinophil Major Basic Protein homolog Classification of C-type Lectins and Proteins with C-type Lectin Domains (CTLDs)

26 XIII - IDD (DGCR2 DiGeorge syndrome critical region gene 2)  IDD (may play a role in so-called “Catch22 syndromes” resulting from deletions on Chromosome 22) XIV - Endosialin  Endosialin Classification of C-type Lectins and Proteins with C-type Lectin Domains (CTLDs)

27 Structure of the CRD-4 of the macrophage mannose receptor (A) and comparison to the CRD-A of the rat mannose-binding protein (MBP-A) (B). Disulfide bonds are shown in pink ball-and-stick representation, and the Ca 2+ is shown as a blue-green sphere. The two segments that connect the extended loop to the core of the CRD, region I (residues 701-708) and region II (residues 729- 734), are shown in yellow. For the MBP-A CRD, Ca 2+ site 1 is the auxiliary site, and Ca 2+ site 2 is the principal site. A B

28 Structures of CRDs in C-type Lectins

29 Recognition of Glycosulfopeptides By P-selectin

30 Similarities in C-type Lectin Domain Structure MBP-C E-Selectin P-Selectin

31 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:  -strands blue, -helices red, and loop regions gold. The disulphide bonds are shown in green as ball-and-stick representation. The Ca 2+ ions bound to MBP-A are drawn as magenta spheres. Ly49A Ly49I NKG2D CD69 CD94 MBP-A

32 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)STRUCTURE AND FUNCTION OF NATURAL KILLER CELL RECEPTORS: Multiple Molecular Solutions to Self, Nonself Discrimination. Annu Rev Immunol 20:853-85


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