hyaluronan and proteoglycans

What is hyaluronan (HA)?

A large, non-sulfated glycosaminoglycan (GAG) made of repeating disaccharides of glucuronic acid and N-acetylglucosamine.

Where is hyaluronan synthesized?

At the plasma membrane by hyaluronan synthases (HAS1, HAS2, HAS3).

What distinguishes HA from other GAGs?

It’s not sulfated, not attached to a core protein, and is synthesized directly at the plasma membrane (not in the Golgi).

What are the linkages in the HA disaccharide?

β1–3 between GlcA and GlcNAc, and β1–4 between GlcNAc and the next GlcA.

What is the typical size of HA in tissues?

Can reach several million Daltons; up to 25,000 disaccharide repeats.

Why is HA highly hydrophilic?

The carboxyl groups on glucuronic acid attract cations and water, forming highly hydrated gels.

Major biological roles of HA?

Structural support, lubrication (synovial fluid), cell migration (especially in development), wound healing, and inflammation modulation.

What are HA’s roles in embryonic development?

Provides a hydrated matrix that facilitates cell migration during processes like heart morphogenesis.

How does HA interact with cells?

Through receptors like CD44 and RHAMM.

Which enzymes degrade HA?

Hyaluronidases (HYAL1, HYAL2, etc.).

Where does HA turnover occur?

Primarily in lymphatics and liver.

Why is HA turnover important?

Maintains tissue homeostasis and prevents fibrosis.

What happens if HA accumulates abnormally?

Can contribute to inflammation, fibrosis, and tumor progression.

What is the difference between high- and low-molecular-weight HA?

High-MW HA is anti-inflammatory and space-filling; low-MW HA fragments are pro-inflammatory and angiogenic.

What is a proteoglycan

A core protein covalently attached to one or more GAG chains.

What are the two main locations of proteoglycans?

Cell surface (e.g., syndecans, glypicans) and extracellular matrix (e.g., aggrecan, perlecan).

What distinguishes CS/DS proteoglycans from HS proteoglycans?

CS/DS contain chondroitin or dermatan sulfate chains; HS contain heparan sulfate chains

What are chondroitin sulfate (CS) disaccharides made of?

Glucuronic acid + N-acetylgalactosamine.

How is dermatan sulfate (DS) derived?

By C5 epimerization of glucuronic acid to iduronic acid in CS chains.

What determines whether a GAG becomes CS/DS or HS?

The first sugar added after the tetrasaccharide linker — GalNAc → CS/DS; GlcNAc → HS.

What is the linker region attaching GAGs to proteins?

Xylose–Gal–Gal–GlcA attached to a serine residue.

Which proteoglycans make up the lectican family?

Aggrecan, versican, neurocan, and brevican.

Common structural features of lecticans?

Core protein with G1 (HA-binding), G2 (spacer), and G3 (C-type lectin) domains; attached CS/KS chains

Which domains are responsible for HA binding and cross-linking?

G1 binds HA; G3 binds tenascins (cross-linkers).

What is aggrecan and where is it found?

large chondroitin sulfate–keratan sulfate proteoglycan abundant in cartilage and brain ECM.

How does aggrecan form aggregates?

Binds to hyaluronan via the G1 domain and is stabilized by link proteins (HAPLN1).

Why is aggrecan important for cartilage?

Provides compressive resistance via osmotic swelling from negative GAG charges.

What is the Donnan effect

Attraction of counterions to the negatively charged GAGs, drawing water into the ECM and creating swelling pressure

What are the main roles of versican?

Found in blood vessels, skin, and heart; involved in cell migration and development

What is neurocan’s function?

Major brain ECM proteoglycan during development; helps structure brain matrix.

What is brevican’s role?

Main adult brain proteoglycan in perineuronal nets (PNNs); regulates plasticity.

What are link proteins (HAPLN family)?

Proteins that stabilize the binding between HA and lecticans; homologous to the G1 domain of lecticans.

What are tenascins?

ECM glycoproteins that bind lectican G3 domains to form cross-linked networks (e.g., tenascin-C, tenascin-R).

how do tenascin-C and tenascin-R differ?

Tenascin-C (hexamer) active in development; Tenascin-R (trimer) stabilizes adult brain ECM.

What are perineuronal nets composed of?

Hyaluronan, aggrecan, brevican, link proteins, and tenascins.

What is the function of PNNs?

Stabilize synaptic connections and restrict plasticity in mature neurons.

How do PNNs provide neuroprotection

By scavenging redox-active metals and limiting neurotoxic factor diffusion.

What happens in the nanomelic chicken mutation?

Loss of aggrecan → no cartilage formation → lethal.

What is cartilage matrix deficiency (CMD) in mice?

Mutation in aggrecan → cartilage defects and perinatal lethality.

What causes brachymorphic mice phenotype?

Mutation in PAPSS2 (sulfate donor enzyme) → under-sulfated CS → short bones

What is Spondyloepiphyseal dysplasia, Kimberley type?

Human heterozygous AGC1 (aggrecan) mutation → short stature and early osteoarthritis

What happens when Neurocan, Brevican, and Tenascins are all knocked out?

Brain still develops normally due to compensatory expression of other lecticans (e.g., versican, aggrecan) and fibrillins.

What are the main functions of lecticans?

Structural support, hydration, regulation of growth factors, and stabilization of ECM.

How do CS/DS sulfation patterns affect function?

Alter binding affinity for signaling molecules like growth factors.

Why is redundancy common among lecticans?

Ensures tissue integrity — especially critical in the brain.