Aggrecan

Aggrecan
250px PDB rendering based on 1tdq.
Identifiers
Symbols	ACAN ; AGC1; AGCAN; CSPG1; CSPGCP; MSK16; SEDK
External IDs	OMIM: 155760 HomoloGene: 136177 GeneCards: ACAN Gene
Gene ontology Molecular function • extracellular matrix structural constituent • protein binding • hyaluronic acid binding • carbohydrate binding • metal ion binding Cellular component • extracellular region • proteinaceous extracellular matrix • Golgi lumen • extracellular matrix • lysosomal lumen Biological process • skeletal system development • carbohydrate metabolic process • proteolysis • cell adhesion • keratan sulfate biosynthetic process • extracellular matrix disassembly • extracellular matrix organization • glycosaminoglycan metabolic process • keratan sulfate metabolic process • keratan sulfate catabolic process • small molecule metabolic process Sources: Amigo / QuickGO
RNA expression pattern
File:PBB GE ACAN 207692 s at tn.png
File:PBB GE ACAN 205679 x at tn.png
File:PBB GE ACAN 217161 x at tn.png
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	176	11595
Ensembl	ENSG00000157766	ENSMUSG00000030607
UniProt	P16112	Q61282
RefSeq (mRNA)	NM_001135	NM_007424
RefSeq (protein)	NP_001126	NP_031450
Location (UCSC)	Chr 15: 88.8 – 88.88 Mb	Chr 7: 79.05 – 79.12 Mb
PubMed search	[1]	[2]

Aggrecan, also known as cartilage-specific proteoglycan core protein (CSPCP) or chondroitin sulfate proteoglycan 1, is a protein that in humans is encoded by the ACAN gene. This gene is a member of the lectican (chondroitin sulfate proteoglycan) family. The encoded protein is an integral part of the extracellular matrix in cartilagenous tissue and it withstands compression in cartilage.

Aggrecan is a proteoglycan, or a protein modified with large carbohydrates; the human form of the protein is 2316 amino acids long and can be expressed in multiple isoforms due to alternative splicing.

Structure

Aggrecan is a high molecular weight (1x10⁶ < M < 3x10⁶) proteoglycan. It exhibits a bottlebrush structure, in which chondroitin sulfate and keratan sulfate glycosaminoglycan (GAG) chains are attached to an extended protein core.

Aggrecan has a molecular mass >2,500 kDa. The core protein (210–250 kDa) has 100–150 GAG chains attached to it.

Aggrecan consists of two globular structural domains (G1 and G2) at the N-terminal end and one globular domain (G3) at the C-terminal end, separated by a large extended domain (CS) heavily modified with GAGs. (N-G1-G2-CS-G3-C) The two main modifier moieties are themselves arranged into distinct regions, a chondroitin sulfate and a keratan sulfate region.

The three globular domains, G1, G2, and G3 are involved in aggregation, hyaluronan binding, cell adhesion, and chondrocyte apoptosis.

Along with type-II collagen, aggrecan forms a major structural component of cartilage, particularly articular cartilage.

The aggrecan family includes other important members such as versican, also named PG-M, neurocan, brevican and the cell surface HA receptor CD44. They are modular proteoglycans containing combinations of structural motifs, such as EGF-like domains, carbohydrate recognition domains (CRD), complement binding protein (CBP)-like domains, immunoglobulin folds and proteoglycan tandem repeats.

Function

Aggrecan is a critical component for cartilage structure and the function of joints.

Functionally, the G1 domain interacts with hyaluronan acid and link protein, forming stable ternary complexes in the extracellular matrix. G2 is homologous to the tandem repeats of G1 and of link protein and is involved in product processing. G3 makes up the carboxyl terminus of the core protein. It enhances glycosaminoglycan modification and product secretion. Aggrecan plays an important role in mediating chondrocyte-chondrocyte and chondrocyte-matrix interactions through its ability to bind hyaluronan.

Aggrecan provides intervertebral disc and cartilage with the ability to resist compressive loads. The localized high concentrations of aggrecan provide the osmotic properties necessary for normal tissue function with the GAGs producing the swelling pressure that counters compressive loads on the tissue. This functional ability is dependent on a high GAG/aggrecan concentration being present in the tissue extracellular matrix. In the disc, aggrecan concentrations peak in a person's twenties, and decline thereafter, with aggrecan degradation products slowly accumulating over the following decades. This causes discs to get stiffer and less resilient with age.

Aggrecan also plays an important role in the organization of the extracellular spaces between neurons in the brain. Through interactions with link protein and tenascins, aggrecan binds to hyaluronan, forming large aggregated complexes at the cell surface.

Clinical significance

The synthesis and degradation of aggrecan are being investigated for their roles in cartilage deterioration during joint injury, disease, and aging.

The linker domain between the N-terminal globular domains, called the interglobular domain, is highly sensitive to proteolysis. Such degradation has been associated with the development of arthritis. Proteases capable of degrading aggrecans are called aggrecanases, and they are members of the ADAM (A Disintegrin And Metalloprotease) protein family.

Degenerative joint disease is a leading source of morbidity resulting in significant social and economic impact. Osteoarthritis is characterized by the slow progressive deterioration of articular cartilage and fibrosis of the synovium and joint capsule. Articular cartilage contains up to 10% proteoglycan by weight, most of which is aggrecan, and its loss is an early sign of the disease.

External links

• Aggrecan at the US National Library of Medicine Medical Subject Headings (MeSH)