Aggrecan

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Aggrecan
Protein ACAN PDB 1tdq.png
PDB rendering based on 1tdq.
Identifiers
Symbols ACAN ; AGC1; AGCAN; CSPG1; CSPGCP; MSK16; SEDK
External IDs OMIM155760 HomoloGene7227 GeneCards: ACAN Gene
RNA expression pattern
PBB GE ACAN 207692 s at tn.png
PBB GE ACAN 205679 x at tn.png
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:
89.35 – 89.42 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.[1] This gene is a member of the aggrecan/versican 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.[1]

Structure[edit]

Aggrecan is a high molecular weight (1x106 < M < 3x106) proteoglycan. It exhibits a bottlebrush structure, in which chondroitin sulfate and keratan sulfate chains are attached to an extended protein core.[2]

Aggrecan has a molecular mass >2,500 kDa.[citation needed] The core protein (210–250 kDa) has 100–150 glycosaminoglycan (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 glycosaminoglycans. (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[edit]

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.[3]

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.[4]

Clinical significance[edit]

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.[5]

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. Cartilage contains up to 10% proteoglycan consisting of mainly the large aggregating chondroitin sulfate proteoglycan aggrecan.

References[edit]

  1. ^ a b Doege KJ, Sasaki M, Kimura T, Yamada Y (January 1991). "Complete coding sequence and deduced primary structure of the human cartilage large aggregating proteoglycan, aggrecan. Human-specific repeats, and additional alternatively spliced forms". J. Biol. Chem. 266 (2): 894–902. PMID 1985970. 
  2. ^ Nap RJ, Szleifer I (November 2008). "Structure and interactions of aggrecans: statistical thermodynamic approach". Biophys. J. 95 (10): 4570–83. doi:10.1529/biophysj.108.133801. PMC 2576360. PMID 18689463. 
  3. ^ Kiani C, Chen L, Wu YJ, Yee AJ, Yang BB (March 2002). "Structure and function of aggrecan". Cell Res. 12 (1): 19–32. doi:10.1038/sj.cr.7290106. PMID 11942407. 
  4. ^ Roughley P, Martens D, Rantakokko J, Alini M, Mwale F, Antoniou J (2006). "The involvement of aggrecan polymorphism in degeneration of human intervertebral disc and articular cartilage". Eur Cell Mater 11: 1–7; discussion 7. PMID 16425147. 
  5. ^ East CJ, Stanton H, Golub SB, Rogerson FM, Fosang AJ (2007). "ADAMTS-5 deficiency does not block aggrecanolysis at preferred cleavage sites in the chondroitin sulfate-rich region of aggrecan". J. Biol. Chem. 282 (12): 8632–40. doi:10.1074/jbc.M605750200. PMID 17255106. 

Further reading[edit]

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