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 MedicineOklahoma Center for Medical Glycobiology

“THE C-TYPE LECTINS”

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

• Ca2+-dependent receptor purified from rabbit liver membranes

– Two subunits, trimeric structure

• Other related proteins purified: trimeric structures with sequence similarities

-ENWGAGEPNNKKSKEDCVEIYIKRERDSGKWNDDACHKRKAALCY-

-TNWNEGEPNNVGSGENCVVLLT-----NGKWNDVPCSDSFLVVCE-Mouse L-selectin

Rat Mannose Binding Protein C

-----------C---------------------------------C---------C-------C-------

LIVMSTA

FYWLIVSTA

—C— —X — —X— —X—X—C—X — —- —C—

n = 5 to 12residues

DNSR

WL

LIVMFYATG

n m

m = 5 to 12residues

Conserved Carbohydrate-Recognition Domain of C-type Lectins

Selectins

Plasma Membrane

Endocytic Receptors

Proteoglycans

Collectins

Lectin Domain

EGF-Like Domain

Complement Regulatory Repeat (Consensus Repeat)

Fibronectin Type II Repeat

OUT

IN

NNNN

N N N

N

C

Variations in Structures of C-type Lectins

“Bouquet”

Examples: Mannose-binding protein A

Surfactant SP-A

“Cruciform”

Examples: Conglutinin Surfactant SP-D

Variations in Structures 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].

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)


Selectins• L-selectin• E-selectin• P-selectin

Lymphocyte lectinsNK receptors (required for MHC-1 recognition)

(the CTLD functions in protein-protein interaction)Ly49A through WNKR-P1CD94/NKG2A/B, -C or -ENKG2DCD69

human mast cell function associated antigen (MCFA)activation-induced C-type lectin (AICL)human eosinophil granule major basic proteinhuman low affinity immunoglobulin epsilon Fc receptor (CD23)P47 or LSLCL (lymphocytic secreted long form of C-type lectin)CIRE (expressed by splenic dendritic cells)


Othershuman integral membrane protein DGCR2/IDDhuman lithostathine 1 precursor (pancreatic stone protein -

PSP)human polycystin human endothelial cell scavenger receptorhuman pancreatitis-associated protein 1 (PAP or HIP)human pancreatic beta cell growth factor (INGAP)

Proteoglycanshuman 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 bindingprotein)

rat neurocan core protein (245 kD early post-natalcoreglycoprotein)


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


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)


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.

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)

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

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


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.

Convergent Evolusion of C-type Lectin Domains (CTLDs)

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


I - ProteoglycansAggrecan (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.)

VersicanNeurocanBrevican Group I

Proteoglycans

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

Sushi Domain

EGFDomain

LinkRegion

GAGDomain

II - Type 2 receptorIgE FcR (CD23)Asialoglycoprotein Receptor Subunit 1Asialoglycoprotein Receptor Subunit 2Macrophage Asialoglycoprotein Receptor Kupffer cell receptorDC immunoreceptorScavenger receptor with CTLDMincleLangerinDC-SIGN; DC-SIGNR Blood Dendritic Cell Antigen 2 (BDCA-2)

Dendritic Lectin CLECSF11 HECL (CLECSF7)

C-type lectin-like receptor CLEC-6

Group IIOligomericType 2Receptors


III - CollectinsMannose-binding protein CPulmonary Surfactant SP-AMannose-binding protein APulmonary Surfactant SP-DCollectin-K1Collectin-L1

IV - SelectinsL-selectinE-SelectinP-selectin

Group IIICollectins

Group IVSelectins


V - NK receptorsDectin-1Mast cell function-associated antigenHNKR-P1ALLT1CD69; CD69 homologCD72CD94KLRF1Oxidised LDL receptorCLEC-1 and -2NKG2 A, C, D, E, HMyeloid DAP12-associating lectin (MDL-1)

Group VDimeric NKCell Receptors


VI - MMR familyMannose ReceptorEndo180Phospholipase-A2 receptorDEC205 (GP200-MR6)

Group VIMannoseReceptors


VII – Free CTLDsLithostathine/Reg 1alphaLithostathine/Reg 1betaPancreatitis-associated protein/HIPPancreatic beta cell Growth FactorRegenerating gene type IV

VIII – Simple Type 1 receptors

LayilinLayilin homolog


Group VIIFree CTLD

IX - Tetranectin Tetranectin (plasminogen-binding protein) Cartilage-derived CTL Stem cell growth factor

X - Polycystin Polycystin


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


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


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.

A B

Structures of CRDs in C-type Lectins

Recognition of GlycosulfopeptidesBy P-selectin

Similarities in C-type Lectin Domain Structure

MBP-C E-Selectin P-Selectin

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 arecolored as follows: -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.

Ly49A Ly49I

NKG2D CD69

CD94 MBP-A

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

essentials of glycobiology lecture 22 may 7, 2002 richard d. cummings, ph.d

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