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Aggrecan

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ACAN
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesACAN, AGC1, AGCAN, CSPG1, CSPGCP, MSK16, SEDK, Aggrecan, SSOAOD
External IDsOMIM: 155760; MGI: 99602; HomoloGene: 136177; GeneCards: ACAN; OMA:ACAN - orthologs
Orthologs
SpeciesHumanMouse
Entrez

176

11595

Ensembl

ENSG00000157766

ENSMUSG00000030607

UniProt

P16112

Q61282

RefSeq (mRNA)

NM_001135
NM_013227
NM_001369268

NM_007424
NM_001361500

RefSeq (protein)

NP_001126
NP_037359
NP_001356197

NP_031450
NP_001348429

Location (UCSC)Chr 15: 88.8 – 88.88 MbChr 7: 78.7 – 78.76 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Aggrecan (ACAN), 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.[5] 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.[5] Aggrecan was named for its ability to form large aggregates in the cartilage tissue (a large aggregating proteoglycan).[6][7]

Structure

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Aggrecan is a high molecular weight (molar mass between 1 million and 3 million) proteoglycan. It exhibits a bottlebrush structure, in which chondroitin sulfate and keratan sulfate glycosaminoglycan (GAG) chains are attached to an extended protein core.[8]

Aggrecan has a molecular mass >2,500 kDa.[9] The core protein (~300 kDa[10]) has around 100 GAG chains attached to it.[11]

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.

Recent molecular simulations and neutron scattering experiments suggested that aggrecan in aqueous solutions forms two-dimensional aggregates that resemble sheet-like shapes.[7]

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

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

Functionally, the G1 domain interacts with hyaluronic 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.[11]

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.[12] In the disc, aggrecan concentrations peak in a person's twenties, and decline thereafter, with aggrecan degradation products slowly accumulating over the following decades.[13] 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.[14] Through interactions with link protein and tenascins, aggrecan binds to hyaluronan, forming large aggregated complexes at the cell surface.

Clinical significance

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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.[15]

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.

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000157766 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000030607 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ 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". Journal of Biological Chemistry. 266 (2): 894–902. doi:10.1016/S0021-9258(17)35257-2. PMID 1985970.
  6. ^ Aspberg A (December 2012). "The different roles of aggrecan interaction domains". The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society. 60 (12): 987–996. doi:10.1369/0022155412464376. PMC 3527881. PMID 23019016.
  7. ^ a b Chremos A, Horkay F (September 2023). "Coexistence of Crumpling and Flat Sheet Conformations in Two-Dimensional Polymer Networks: An Understanding of Aggrecan Self-Assembly". Physical Review Letters. 131 (13): 138101. Bibcode:2023PhRvL.131m8101C. doi:10.1103/PhysRevLett.131.138101. PMID 37832020. S2CID 263252529.
  8. ^ Nap RJ, Szleifer I (November 2008). "Structure and interactions of aggrecans: statistical thermodynamic approach". Biophysical Journal. 95 (10): 4570–4583. Bibcode:2008BpJ....95.4570N. doi:10.1529/biophysj.108.133801. PMC 2576360. PMID 18689463.
  9. ^ Hascall V, Sajdera S (10 October 1970). "Physical properties and polydispersity of proteoglycan from bovine nasal cartilage". The Journal of Biological Chemistry. 245 (19): 4920–4930. doi:10.1016/S0021-9258(18)62796-6. PMID 5506265.
  10. ^ Chandran P, Horkay F (January 2012). "Aggrecan, an unusual polyelectrolyte: review of solution behavior and physiological implications". Acta Biomaterialia. 8 (1): 3–12. doi:10.1016/j.actbio.2011.08.011. PMC 3226867. PMID 21884828.
  11. ^ a b Kiani C, Chen L, Wu YJ, Yee AJ, Yang BB (March 2002). "Structure and function of aggrecan". Cell Research. 12 (1): 19–32. doi:10.1038/sj.cr.7290106. PMID 11942407.
  12. ^ Roughley P, Martens D, Rantakokko J, Alini M, Mwale F, Antoniou J (Jan 2006). "The involvement of aggrecan polymorphism in degeneration of human intervertebral disc and articular cartilage". European Cells & Materials. 11: 1–7, discussion 7. doi:10.22203/eCM.v011a01. PMID 16425147.
  13. ^ Sivan SS, Wachtel E, Roughley P (Oct 2014). "Structure, function, aging and turnover of aggrecan in the intervertebral disc". Biochimica et Biophysica Acta. 1840 (10): 3181–3189. doi:10.1016/j.bbagen.2014.07.013. PMID 25065289.
  14. ^ Morawski M, Brückner G, Arendt T, Matthews RT (May 2012). "Aggrecan: Beyond cartilage and into the brain". The International Journal of Biochemistry & Cell Biology. 44 (5): 690–693. doi:10.1016/j.biocel.2012.01.010. PMID 22297263.
  15. ^ East CJ, Stanton H, Golub SB, Rogerson FM, Fosang AJ (Mar 2007). "ADAMTS-5 deficiency does not block aggrecanolysis at preferred cleavage sites in the chondroitin sulfate-rich region of aggrecan". Journal of Biological Chemistry. 282 (12): 8632–8640. doi:10.1074/jbc.M605750200. PMID 17255106.

Further reading

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