7.3 Glycoconjugates: Proteoglycans, glycoproteins, and Glycolipids

Glycoconjugate

Roles of glycoconjugate (information carriers) Signal transduction (by recognition extracellular signal or parasites) Cell-cell & cell-ECM communications Protein labeling for translocation and degradation

Proteoglycan Sulfated glycosaminoglycan-attached membrane proteins (cell surface) or

secreted protein (ECM) Glycosaminoglycan is the major part

Binding sites for other proteins (electrostatic interactions) Major components of connective tissue providing strength and resilience

Glycoproteins Oligosaccharide-attached proteins Outer face of plasma membrane, ECM, blood Inside cells; golgi, secretory granules, lysosomes Specific sites for recognition (information-rich oligosaccharide)

Glycolipids Membrane sphingolipids; oligosaccharide on hydrophilic head groups Specific site for recognition

Proteoglycan

Roles of proteoglycan 40 types in mammalian cells Tissue organizer

Development of specialized tissues Mediating growth factor activity Regulating extracellular assembly of collagen fibrils

Structure Core protein-tetrasaccharide bridge-glycosaminoglycan Secretion to ECM or integration to the membrane

e.g. Syndecans and glypicans

Proteoglycan

Domain structure of heparan sulfate

- Modulation of ligand – receptor interactions at cell surface

- Highly sulfated domains (NS) vs. unmodified domains (NA)

- Variation of sulfation pattern in NS domain among proteoglycan

Heparan Sulfate

Protein interactions with NS domains of heparan sulfate

Proteoglycan Aggregates

Structure Many aggrecans + single hyaluronate Proteoglycan aggregates Mr> 2 X 108

Function Strong interaction with fibrous matrix

proteins (collagen, elastin, fibronectin) in ECM Tensile strength, resilience Anchoring cell to ECM Cell-cell interaction, migration

Glycoproteins

Glycosylation to proteins O-linked glycosylation : Ser, Thr N-linked glycosylation : Asn

Types of glycoproteins Membrane proteins Secreted proteins Antibody, hormones, milk proteins

(lactalbumin), proteins released by the pancreas, lysosomal proteins

Advantages of oligosaccharide attachment Hydrophilicity (polarity & solubility) Destination label Label for protein quality control Protein folding Protection from proteolytic attacks Informational roles (recognition &

communication)

Glycolipids and Lipopolysaccharides

Gangliosides Eukaryotic membrane lipid

with oligosaccharide containing a sialic acid and monosaccharides in the lipid head group E.g. blood typing

Lipopolysaccharides Structure in the outer

surface of gram(-) bacteria (Escherichia coli, Salmonella typhimrium)

Prime immunological target against bacterial infections

Some are toxic to animals

7.4 Carbohydrates as Informational Molecules : The Sugar Code

Lectins

Biological functions Cell-cell recognition/ Signaling/ Adhesion/ Intracellular targeting of

newly synthesized proteins Detection and separation of glycoproteins

Carbohydrate-binding proteins with high affinity and specificity

Half-Life regulation of hormones

Luteinizing hormone and thyrotropin Peptide hormones produced in the pituitary N-linked glycosylation ending with GalNA4S (14)GlcNAc Recognized by a lectin of hepatocytes

Uptake and degradation Periodic rise and fall

Glycoproteins with sialic acid at the end Protected from degradation in the liver (e.g. ceruloplasmin,

erythrocytes) Removal of sialic acid by sialidase (neuraminidase) from old

proteins Recognition of unprotected Gal by asialoglycoprotein receptor

in the liver Endocytosis and degradation

Lectins in development of diseases

Selectins (plasma membrane lectins) mediating cell-cell recognition and adhesion Movement of neutrophils through the

capillary wall to tissues at sites of infection or inflammation P-selectin on capillary endothelial cell

surface binds to glycoprotein of neutrophils slow-down neutrophils movement along the capillary

Interaction between integrin on capillary endothelial cell surface and ligand on neutrophils Stops neutrophils rolling, and begins extravasation into infected tissue

Mediation of inflammatory responses - rheumatoid arthritis, asthma, psoriasis,

transplantation rejection

Lectins in development of diseases

Hemagglutinin (lectin of influenza virus) Essential for viral entry and infection Interaction with sialic acid residue

from host cell’s oligosaccharides entry & bud-out

Sialidase (neuramidase) Cleavage of sialic acid releasing

viral particles Target for antiviral drugs e.g) Tamiflu, Relenza

Lectins of herpes simplex viruses Interaction with heparan sulfate on

host cell surface Sulfation pattern dependency target for drug development

Bacterial Adhesion by Lectins

Helicobacter pylori Responsible for gastric ulcers Bacterial membrane lectins Interaction with oligosaccharide Lewis b of

gastric epithelial cells Part of the type O blood group determinant Greater incidence of gastric ulcer in people

of blood type O Leb analogues as potential drugs

Toxins (lectins) Vibrio cholerae toxin (cholera toxin)

Attach to oligosaccharide of ganglioside GM1 on the surface of host epithelial cell

Bordetella pertussis toxin Enters target cells after interacting with host

oligosaccharide with a terminal sialic acid Toxin analogs without carbohydrate binding site as

potential vaccines

Intracellular Lectins

Mannose 6-P receptor Membrane-associated lectin on the lumenal

side of golgi complex Interaction with mannose 6-P-containing

proteins transport vesicle to fuse lysosome Targeting mechanism of most enzyme in

lysosome

ER lectins Calnexin (membrane) & calreticulin (soluble) Induce native folding of new proteins Protein quality control Glycosylation as quality control signals ERGIC53; transport folded proteins to golgi

complex (maturation) EDEM; transport abnormally folded proteins to

cytosol (degradation)

Lectin-Carbohydrate Interactions

Strong and specific interactions Hydrogen bonding Van der Waals interactions Salt bridge

General interactions Hydrophobic interactions

Sialic acid - Sialoadhesin

Mannose-6-P with receptor

Roles of Oligosaccharide Recognition and Adhesion at the Cell Surface