Proteoglycans & Glycoproteins (DLA)

What are Glycoproteins?

Consists mainly of protein + Small sugar chains (often branched). Sugars linked via O- and N- glycosylations.

What are Proteoglycans?

Glycoproteins that have a higher carbohydrate content, typically featuring long chains of repeating disaccharide units, and are important in cellular communication and tissue structure.

What are glycoproteins composed of?

Glycoproteins consist mainly of protein and small sugar chains (often branched), with sugars linked via O- and N-glycosylations.

Structure of proteoglycans.

Proteoglycans are composed of long, unbranched polysaccharide chains (glycosaminoglycans) and a small amount of protein.

GAGs attached to protein core via

O-glycosidic bonds between -OH group of serine & sugar.

Composition of Glycosaminoglycans (GAGs)

GAGs are long repeating units of unbranched disaccharides.

General structure of repeating disaccharide units:

Negatively charged Sugars→

GAG chains radiate out from protein core

Types of GAGs

Heparan sulfate (HS), Chondroitin 4- or 6-sulfates (CS), Dermatan sulfate (DS), Keratan sulfate (KS)

Permutations of these monosaccharides gives rise to

different GAG families with unique properties, functions, locations and names.

Conjugated to protein cores to form

proteoglycans

Hyaluronan/ hyaluronic acid (HA) and Heparin (Hep)

Free GAGs

Extracellular GAGS

Located throughout ECM & on cell membranes in all tissues

Intracellular GAGs

Heparin; within mast cells

What is the structure of a proteoglycan monomer?

A proteoglycan contains more than 100 GAG chains, where a single GAG chain can contain up to 200 disaccharide units.

How are GAGs linked to the core protein in proteoglycans?

GAGs are covalently linked to serine residues of the core protein via O-glycosylation.

Can the GAG chains on a single proteoglycan monomer differ?

Yes, the GAG chains on a single monomer can differ.

What is the effect of the high number of negative charges on GAGs in proteoglycans?

The high number of negative charges on GAGs causes extension of each chain, repulsion between chains (resulting in a bottle-brush appearance), and binds water.

What is the significance of water binding in proteoglycans?

Binding of water generates a hydrated gel, which is significant for flexible support of the extracellular matrix (ECM), tissue hydration, lubrication, shock absorption, and serves as a molecular sieve.

What are some functions of glycosaminoglycans (GAGs) on cell surfaces?

GAGs play roles in sequestration of proteins, binding to and modifying the activity of enzymes, chemokines, growth factors, coagulation factors, and amyloid precursor proteins.

How do GAGs influence cell signaling?

GAGs can influence various aspects of cell signaling, including cell migration, growth factor signaling, synaptogenesis, and vesicular trafficking.

What role do GAGs play in the extracellular matrix (ECM)?

GAGs are involved in the regulation and protection of the ECM as well as modulation of tissue mechanical properties and regulation of cell-to-cell interactions.

How do GAGs affect viral infections?

GAGs can regulate viral infections by interacting with viral particles and influencing their ability to infect cells.

What do proteoglycan aggregates in the extracellular matrix (ECM) help form?

Proteoglycan aggregates contribute to the ground substance of the ECM, which includes structural proteins (collagen and elastin) and multi-adhesive glycoproteins (such as fibronectin and laminin).

What is the composition of the ground substance in the extracellular matrix?

The ground substance in the ECM is composed of proteoglycan aggregates and multi-adhesive glycoproteins like fibronectin and laminin.

In which tissues is hyaluronic acid (HA) found?

Hyaluronic acid is found in the vitreous humor of the eye, synovial fluid of joints, cartilage, and loose connective tissues.

What is the composition of vitreous humor?

The vitreous humor is composed of 98% water and 2% hyaluronic acid.

What role does hyaluronic acid play in cell migration?

Hyaluronic acid facilitates cell migration during embryogenesis (neural tube closure), morphogenesis, and wound repair.

What are the functions of hyaluronic acid (HA) alone?

Hyaluronic acid functions in hydration, lubrication of joints, space filling capacity, and as a framework through which cells migrate.

How do proteoglycan aggregates contribute to tissues?

Proteoglycan aggregates (HA + proteoglycan monomers) contribute to the structural and mechanical properties of tissues.

What is the structure of Chondroitin Sulfate?

Chondroitin Sulfate is composed of disaccharide units consisting of an acidic sugar and a N-acetylated amino sugar.

Where is Chondroitin Sulfate commonly found?

Chondroitin Sulfate is found in bone, cartilage, tendons, ligaments, and the aorta.

How does Chondroitin Sulfate form proteoglycan aggregates?

Chondroitin Sulfate forms proteoglycan aggregates through non-covalent association with hyaluronic acid.

What is a common use of Chondroitin Sulfate in dietary supplementation?

Chondroitin Sulfate is commonly used in dietary supplementation for the treatment of osteoarthritis.

What is the structure of Dermatan Sulfate?

Dermatan Sulfate consists of disaccharide units made up of an acidic sugar and an N-acetylated amino sugar.

Where is Dermatan Sulfate abundant?

Dermatan Sulfate is abundant in skin, cartilage, blood vessels, and heart valves.

What is the primary function of Heparan Sulfate?

Heparan Sulfate is found in basement membranes and is common on cell surfaces, playing a role in cell-cell recognition.

What is the structure of Heparan Sulfate?

Heparan Sulfate consists of disaccharide units made up of an acidic sugar and an N-acetylated amino sugar.

What are Mucopolysaccharidoses?

Mucopolysaccharidoses (MPS) are inherited deficiencies in one of the acid hydrolases required for lysosomal degradation of GAGs.

What are the consequences of Hunter and Hurler Syndrome?

Hunter and Hurler Syndrome result in the accumulation of dermatan and heparan sulfate, leading to lysosomal GAG accumulation, skeletal deformities, hepatomegaly, and intellectual disability.

Where is Heparin found intracellularly?

Heparin is found in mast cell granules in the arteries of the lung, liver, and spleen.

What is the primary function of Heparin?

Heparin acts as an anticoagulant by inhibiting thrombin and preventing clotting.

What is the structure of Heparin?

Heparin consists of disaccharide units made of an acidic sugar and an amino sugar. It is highly sulfated and negatively charged.

What are the therapeutic uses of Heparin?

Heparin is used to prevent and treat thrombotic events such as deep vein thrombosis (DVT), pulmonary embolism (PE), and atrial fibrillation (AF).

What are Glycoproteins?

Glycoproteins are proteins that have carbohydrates attached via O-linked or N-linked glycosylation.

How are carbohydrates attached in O-linked glycosylation?

In O-linked glycosylation, sugars are attached via the OH groups of serine, threonine, or hydroxy-lysine residues.

How are carbohydrates attached in N-linked glycosylation?

In N-linked glycosylation, sugars are attached via the amide N group on the side chain of asparagine residues.

What is O-Glycosylation of Proteins?

O-Glycosylation occurs when a sugar is enzymatically linked directly to the OH group of serine, threonine, or hydroxylysine residues in the rough endoplasmic reticulum (ER) lumen.

Where does O-Glycosylation occur in the cell?

O-Glycosylation occurs in the rough endoplasmic reticulum (RER), and subsequent sugar additions take place in the Golgi apparatus, where glycosyltransferases are present.

What role do Glycosyltransferases play in O-Glycosylation?

Glycosyltransferases are enzymes that catalyze the initial linkage of the first sugar to the OH groups of serine, threonine, or hydroxylysine during O-glycosylation in the RER.

What happens to the signal sequence during the process of O-Glycosylation?

The signal sequence is cleaved after the mRNA is translated and the protein is transported to the rough endoplasmic reticulum (RER).

Examples of O-Glycosylation

Proteoglycans, collagen, glycocalyx components, blood group substances, and mucins.

Blood Group Substances

Antigen A, Antigen B, Antigen H

What are N-linked Glycoproteins?

N-linked glycoproteins are glycoproteins in which only asparagine residues are N-glycosylated.

What is the role of dolichol-pyrophosphate in N-glycosylation?

N-glycosylation requires dolichol-pyrophosphate, which serves as a lipid carrier for the synthesis of a mannose-rich oligosaccharide.

What is synthesized bound to dolichol-PP?

A mannose-rich oligosaccharide is synthesized bound to the lipid dolichol-pyrophosphate.

What are the biological functions of N-linked glycoproteins?

The biological functions of N-linked glycoproteins include protein folding, protein trafficking, and signal transduction.

What is N-Glycosylation of Proteins?

N-Glycosylation occurs in the rough endoplasmic reticulum (RER) where a mannose-rich oligosaccharide is transferred to a specific asparagine residue of the protein to be N-glycosylated.

What happens to the sugar residues during N-Glycosylation?

After the mannose-rich oligosaccharide is transferred, trimming of sugar residues occurs in the RER.

Where do further modifications of N-Glycosylated proteins occur?

Further modifications of N-Glycosylated proteins occur in the Golgi apparatus.

Fates of N-linked Glycoproteins

Secretion, Lysosomes, Cell Membrane Proteins

What is the role of Mannose 6-Phosphate in the transport of lysosomal enzymes?

Lysosomal enzymes are N-linked glycoproteins that receive a Mannose 6-Phosphate marker in the cis-Golgi for transport into lysosomes.

How is the Mannose 6-P marker formed?

The Mannose 6-P marker is formed by a specific phosphotransferase that recognizes all enzymes destined to be transported into lysosomes.

What is the function of Mannose 6-P receptors?

Mannose 6-P receptors in the trans-Golgi bind the marked enzymes and package them into vesicles for transport into lysosomes.

What is I-Cell disease and how is it related to Mannose 6-Phosphate?

A deficiency of the Mannose 6-P marker leads to I-Cell disease, where potential lysosomal enzymes are lacking in lysosomes and are instead secreted into plasma and urine, manifesting at birth and often resulting

What is I-Cell disease?

I-Cell disease, also known as mucolipidosis Type II, is a lysosomal storage disease characterized by the lack of several enzymes in lysosomes, resulting in the accumulation of macromolecules.

What happens to enzymes destined for lysosomes in I-Cell disease?

In I-Cell disease, enzymes that are meant for lysosomes are instead secreted into the bloodstream, leading to incomplete degradation of various macromolecules.

What are the consequences of enzyme deficiency in I-Cell disease?

The lack of lysosomal enzymes results in the accumulation of complex lipids and glycosaminoglycans (GAGs), forming inclusion bodies within the cells.

How is I-Cell disease diagnosed?

Diagnosis of I-Cell disease is based on the identification of inclusions in peripheral blood lymphocytes or cultured skin fibroblasts, confirmed by assessing lysosomal enzyme activity in blood.

What are the clinical features of I-Cell disease?

Clinical features of I-Cell disease are similar to those of mucopolysaccharidoses or sphingolipidoses, characterized by various systemic complications.