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ESSENTIALS OF GLYCOBIOLOGY LECTURE 22 MAY 7, 2002 Richard D. Cummings, Ph.D.

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 ”. Ashwell and Morell 1960s and 1970s

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ESSENTIALS OF GLYCOBIOLOGY LECTURE 22 MAY 7, 2002 Richard D. Cummings, Ph.D.

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  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. 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 Ca2+-dependent receptor purified from rabbit liver membranes Two subunits, trimeric structure Other related proteins purified: trimeric structures with sequence similarities Prototype C-type lectin: Asialoglycoprotein receptor

  3. 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 -----------C---------------------------------C---------C-------C------- Conserved Carbohydrate-Recognition Domain of C-type Lectins Rat Mannose Binding Protein C -ENWGAGEPNNKKSKEDCVEIYIKRERDSGKWNDDACHKRKAALCY- -TNWNEGEPNNVGSGENCVVLLT-----NGKWNDVPCSDSFLVVCE- Mouse L-selectin

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

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

  6. Types of C-type Lectins • 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].

  7. Types of C-type Lectins • 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)

  8. Types of C-type Lectins • 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)

  9. Types of C-type Lectins • 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) • Others • 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)

  10. Types of C-type Lectins • 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

  11. 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)

  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 Ca2+ and Cl are indicated by the green and blue balls, respectively. Note that Ca2+ is closely coordinated with the bound sugar.

  13. 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)

  14. Ca2+-Coordination by C-type Lectins 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. Ca2+-Coordination by C-type Lectins 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

  16. Convergent Evolusion of C-type Lectin Domains (CTLDs) C-type lectin-like domains (CTLDs) of higher eukaryotes are protein modules originally identified as carbohydrate-recognition domains (CRDs) in a family of Ca2+-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.

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

  18. Group I Proteoglycans Classification of C-type Lectins and Proteins with C-type Lectin Domains (CTLDs) Sushi Domain 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 EGF Domain GAG Domain Link Region

  19. Group II Oligomeric Type 2 Receptors Classification of C-type Lectins and Proteins with C-type Lectin Domains (CTLDs) 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

  20. Group IV Selectins Group III Collectins Classification of C-type Lectins and Proteins with C-type Lectin Domains (CTLDs) 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

  21. Group V Dimeric NK Cell Receptors Classification of C-type Lectins and Proteins with C-type Lectin Domains (CTLDs) 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)

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

  23. Group VII Free CTLD Classification of C-type Lectins and Proteins with C-type Lectin Domains (CTLDs) 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

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

  25. Classification of C-type Lectins and Proteins with C-type Lectin Domains (CTLDs) 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

  26. Classification of C-type Lectins and Proteins with C-type Lectin Domains (CTLDs) 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

  27. A B 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 Ca2+ 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, Ca2+ site 1 is the auxiliary site, and Ca2+ site 2 is the principal site.

  28. Structures of CRDs in C-type Lectins

  29. Recognition of Glycosulfopeptides By P-selectin

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

  31. 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

  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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