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 ACANgene. 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 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.
Aggrecan has a molecular mass >2,500 kDa. The core protein (210–250 kDa) has 100–150 glycosaminoglycan (GAG) chains attached to it.
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 source | 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.
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.
Clinical significance[edit source | edit]
The synthesis and degradation of aggrecan are being investigated for their roles in cartilage deterioration during joint injury, disease, and aging.
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.
^ abDoege 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. PMID1985970.
^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 Mater11: 1–7; discussion 7. PMID16425147.
^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. PMID17255106.
^Matsumoto K, Shionyu M, Go M, Shimizu K, Shinomura T, Kimata K, Watanabe H (October 2003). "Distinct interaction of versican/PG-M with hyaluronan and link protein". J. Biol. Chem.278 (42): 41205–12. doi:10.1074/jbc.M305060200. PMID12888576.
Further reading[edit source | edit]
Watanabe H, Yamada Y, Kimata K (1999). "Roles of aggrecan, a large chondroitin sulfate proteoglycan, in cartilage structure and function.". J. Biochem.124 (4): 687–93. PMID9756610.
Fosang AJ, Neame PJ, Last K, et al. (1992). "The interglobular domain of cartilage aggrecan is cleaved by PUMP, gelatinases, and cathepsin B.". J. Biol. Chem.267 (27): 19470–4. PMID1326552.
Baldwin CT, Reginato AM, Prockop DJ (1989). "A new epidermal growth factor-like domain in the human core protein for the large cartilage-specific proteoglycan. Evidence for alternative splicing of the domain.". J. Biol. Chem.264 (27): 15747–50. PMID2789216.
Kimata K, Barrach HJ, Brown KS, Pennypacker JP (1981). "Absence of proteoglycan core protein in cartilage from the cmd/cmd (cartilage matrix deficiency) mouse.". J. Biol. Chem.256 (13): 6961–8. PMID7240256.
Glumoff V, Savontaus M, Vehanen J, Vuorio E (1994). "Analysis of aggrecan and tenascin gene expression in mouse skeletal tissues by northern and in situ hybridization using species specific cDNA probes.". Biochim. Biophys. Acta1219 (3): 613–22. doi:10.1016/0167-4781(94)90220-8. PMID7524681.
Ilic MZ, Mok MT, Williamson OD, et al. (1995). "Catabolism of aggrecan by explant cultures of human articular cartilage in the presence of retinoic acid.". Arch. Biochem. Biophys.322 (1): 22–30. doi:10.1006/abbi.1995.1431. PMID7574678.
Korenberg JR, Chen XN, Doege K, et al. (1993). "Assignment of the human aggrecan gene (AGC1) to 15q26 using fluorescence in situ hybridization analysis.". Genomics16 (2): 546–8. doi:10.1006/geno.1993.1228. PMID8314595.
Kirschfink M, Blase L, Engelmann S, Schwartz-Albiez R (1997). "Secreted chondroitin sulfate proteoglycan of human B cell lines binds to the complement protein C1q and inhibits complex formation of C1.". J. Immunol.158 (3): 1324–31. PMID9013976.
Parkar AA, Kahmann JD, Howat SL, et al. (1998). "TSG-6 interacts with hyaluronan and aggrecan in a pH-dependent manner via a common functional element: implications for its regulation in inflamed cartilage.". FEBS Lett.428 (3): 171–6. doi:10.1016/S0014-5793(98)00523-7. PMID9654129.