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Aggrecan (CSPCP) Proteins

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Aggrecan (CSPCP) Proteins

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Aggrecan (CSPCP) Proteins Background

Aggrecan is a large aggrecan, which is one of the main structural components of cartilage. Its core protein contains three glycolipid domains and two glycosaminoglycan linking domains. These domains play various roles in maintaining cartilage structure and function. The N-terminal globular domain binds hyaluronic acid and links proteins to form huge aggregates. Chondroitin sulfate (CS) chains are connected to the CS domain and provide a hydrated viscous gel that absorbs compressive loads. Two types of autosomal recessive cartilage dysplasia, mouse cartilage matrix deficiency (cmd), and chicken nanotumor disease are caused by mutations in the proteoglycan gene. Cmd homozygotes die shortly after birth, while heterozygotes are born normally. However, cmd heterozygotes develop into late onset of spinal disease, suggesting that aggrecan is a candidate gene that makes individuals susceptible to spinal problems. Nanomelia is a useful model for elucidating intracellular transport of proteoglycans. Further research on aggrecan will lead to the prevention and treatment of joint destructive diseases such as osteoarthritis and clarify cartilage development, which is essential for bone formation.

Aggrecan (CSPCP) Proteins Figure 1. Structure of the ACAN protein.

Keratin sulfate

Keratin sulfate, also known as keratin sulfate, forms a conjugate with proteins and is found in mammalian cornea, intervertebral plates, cartilage and arteries, which is a mucopolysaccharide in the form of proteoglgcan. In most cases, it coexists with chondroitin sulfate, and sometimes there is only one protein part. Proteoglycans in fetal cartilage hardly contain keratan sulfate, but their content increases with age, which can be used as an example of changes in connective tissue of animals with age. As shown in the figure, keratan sulfate uses disaccharides formed by D-galactose and N-acetylglucosamine-6-sulfuric acid as the main repeating unit, and a part of galactose is sulfated or branched into another at the 6 position Sugar chain. Some keratan sulfates also contain a small amount of fucose, aluminosilicic acid, this fine heterogeneous structure, which is tissue specific. In terms of protein-bound forms, keratan sulfate in the cornea is N-acetylglucosamine and aspartic acid is bound by N-glycoside bonds, while keratan sulfate in cartilage and other skeletal systems is N-acetylglucosamine. Amine, serine and methionine are different from each other by O-glycosidic bonds. In either case, several molecules of mannose are still present near the binding region.

Aggrecan (CSPCP) Proteins Figure 2. Chemical structure of keratan sulfate.

Chondroitin sulfate (CS)

Chondroitin sulfate (CS) is a class of glycosaminoglycans that are covalently linked to proteins to form proteoglycans. Chondroitin sulfate is widely distributed on the extracellular matrix and cell surface of animal tissues. The sugar chain is composed of alternating glucuronic acid and N-acetylgalactosamine (also known as N-acetylgalactosamine) disaccharide units. The linking region is connected to the serine residue of the core protein. Chondroitin sulfate exists in all organisms from nematodes to humans except plants, and plays many important physiological functions. Although the structure of the main chain of the polysaccharide is not complicated, the degree of sulfated, sulfate group and two kinds of differences in the distribution of the isouronic acid rechain are highly heterogeneous. The fine structure of chondroitin sulfate determines the specificity of the function and its interaction with various protein molecules.

Aggrecan (CSPCP) Proteins Figure 3. Chemical structure of one unit in a chondroitin sulfate chain.

Transcriptional regulation

Because the expression of cartilage aggrecan is very specific, studies on the transcription of the cartilage aggrecan gene may clarify the mechanism of chondrocyte differentiation. In rats (23), mice (25), and chickens (51), transcription start sites for aggrecan genes were identified. Si nuclease protection and/or primer extension showed two, four, and three transcription start sites in rats, mice, and chickens, respectively. The aggrecan promoter in any species does not have a TATA sequence. The mouse promoter contains two glucocorticoid receptor binding sequences (TGTTCT/C), a GGGCGG sequence (Sp-1 site) and several homologous direct repeat sequences. In addition, the sequence in one region between -54 to -111 showed sequence homology with the sequence of the rat type II collagen promoter (-103 to -132). This sequence is highly conserved in rat and mouse type II collagen genes (52), and is very important for the type II collagen gene promoter activity. Another segment of the sequence from -287 to -259 shows homology to the sequence (-82 to -60) of the rat connexin promoter. These sequences may play a role in cartilage-specific gene expression. In rats, the 922 bp fragment containing 640 bp 5 'flanking DNA and 282 bp exon 1 showed higher promoter activity in transfected chondrocytes than in fibroblasts. In chicken, 1.8 kb genomic fragment at the 5 'end of aggrecan gene can drive tissue-specific expression the way. The 1.8 kb fragment of the chicken aggrecan promoter and exon 1 contains four CACACA motifs. Mouse aggrecan exon 1 contains two E-box themes. Overexpression of sclera, helix-loop-helix transcription factor, enhances aggrecan gene expression of osteoblasts ROS cells through its site.

Functions

Aggrecan is a key component of cartilage structure and joint function. Functionally, the G1 domain interacts with hyaluronic acid and connects proteins to form a stable ternary complex in the extracellular matrix. G2 is homologous to the tandem repeats of G1 and connexin and is involved in product processing. G3 constitutes the carboxy 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 hyaluronic acid.

Clinical significance

Degenerative joint disease is a major source of morbidity leading to major social and economic impacts. 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:

  1. Doege KJ, et al.; 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. 1991, 266 (2): 894–902.
  2. Hideto Watanabe, et al.; Roles of Aggrecan, a Large Chondroitin Sulfate Proteoglycan, in Cartilage Structure and Function. J. Biochem. 1998, 124, 687-693 (1998)

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