Aggrecan

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

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

Structure
Aggrecan is a high molecular weight (1x106 < M < 3x106) proteoglycan. It exhibits a bottlebrush structure, in which is_associated_with::chondroitin sulfate and is_associated_with::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 is_associated_with::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 is_associated_with::chondroitin sulfate and a is_associated_with::keratan sulfate region.

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

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

The aggrecan family includes other important members such as is_associated_with::versican, also named PG-M, is_associated_with::neurocan, is_associated_with::brevican and the cell surface HA receptor is_associated_with::CD44. They are modular proteoglycans containing combinations of structural motifs, such as is_associated_with::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 is_associated_with::brain. Through interactions with is_associated_with::link protein and tenascins, aggrecan binds to is_associated_with::hyaluronan, forming large aggregated complexes at the cell surface.

Clinical significance
The synthesis and degradation of aggrecan are being investigated for their roles in is_associated_with::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 is_associated_with::proteolysis. Such degradation has been associated with the development of is_associated_with::arthritis. is_associated_with::Proteases capable of degrading aggrecans are called is_associated_with::aggrecanases, and they are members of the ADAM (A is_associated_with::Disintegrin And is_associated_with::Metalloprotease) protein family.

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