Aggrecan

Last updated
ACAN
Protein ACAN PDB 1tdq.png
Available structures
PDB Human UniProt search: PDBe RCSB
Identifiers
Aliases ACAN , AGC1, AGCAN, CSPG1, CSPGCP, MSK16, SEDK, Aggrecan, SSOAOD
External IDs OMIM: 155760 HomoloGene: 136177 GeneCards: ACAN
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001135
NM_013227
NM_001369268

n/a

RefSeq (protein)

NP_001126
NP_037359
NP_001356197

n/a

Location (UCSC) Chr 15: 88.8 – 88.88 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human

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. [3] 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.

Contents

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. [3] Aggrecan was named for its ability to form large aggregates in the cartilage tissue (a large aggregating proteoglycan). [4] [5]

Structure

Aggrecan is a high molecular weight (1x106 < M < 3x106) proteoglycan. It exhibits a bottlebrush structure, in which chondroitin sulfate and keratan sulfate glycosaminoglycan (GAG) chains are attached to an extended protein core. [6]

Aggrecan has a molecular mass >2,500 kDa. [7] The core protein (~300 kDa [8] ) has around 100 GAG chains attached to it. [9]

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. [5]

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

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. [9]

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. [10] In the disc, aggrecan concentrations peak in a person's twenties, and decline thereafter, with aggrecan degradation products slowly accumulating over the following decades. [11] 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. [12] Through interactions with link protein and tenascins, aggrecan binds to hyaluronan, forming large aggregated complexes at the cell surface.

Clinical significance

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. [13]

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.

Related Research Articles

<span class="mw-page-title-main">Cartilage</span> Resilient and smooth elastic tissue in animals

Cartilage is a resilient and smooth type of connective tissue. It is a semi-transparent and non-porous type of tissue. It is usually covered by a tough and fibrous membrane called perichondrium. In tetrapods, it covers and protects the ends of long bones at the joints as articular cartilage, and is a structural component of many body parts including the rib cage, the neck and the bronchial tubes, and the intervertebral discs. In other taxa, such as chondrichthyans, but also in cyclostomes, it may constitute a much greater proportion of the skeleton. It is not as hard and rigid as bone, but it is much stiffer and much less flexible than muscle. The matrix of cartilage is made up of glycosaminoglycans, proteoglycans, collagen fibers and, sometimes, elastin. It usually grows quicker than bone.

<span class="mw-page-title-main">Chondroitin sulfate</span> Sulfated glycosaminoglycan (GAG) compound

Chondroitin sulfate is a sulfated glycosaminoglycan (GAG) composed of a chain of alternating sugars. It is usually found attached to proteins as part of a proteoglycan. A chondroitin chain can have over 100 individual sugars, each of which can be sulfated in variable positions and quantities. Chondroitin sulfate is an important structural component of cartilage, and provides much of its resistance to compression. Along with glucosamine, chondroitin sulfate has become a widely used dietary supplement for treatment of osteoarthritis, although large clinical trials failed to demonstrate any symptomatic benefit of chondroitin.

<span class="mw-page-title-main">Chondrocyte</span> Cell that makes up cartilage

Chondrocytes are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans. Although the word chondroblast is commonly used to describe an immature chondrocyte, the term is imprecise, since the progenitor of chondrocytes can differentiate into various cell types, including osteoblasts.

<span class="mw-page-title-main">Versican</span> Protein-coding gene in the species Homo sapiens

Versican is a large extracellular matrix proteoglycan that is present in a variety of human tissues. It is encoded by the VCAN gene.

<span class="mw-page-title-main">Keratan sulfate</span> Class of chemical compounds

Keratan sulfate (KS), also called keratosulfate, is any of several sulfated glycosaminoglycans that have been found especially in the cornea, cartilage, and bone. It is also synthesized in the central nervous system where it participates both in development and in the glial scar formation following an injury. Keratan sulfates are large, highly hydrated molecules which in joints can act as a cushion to absorb mechanical shock.

<span class="mw-page-title-main">Perlecan</span>

Perlecan (PLC) also known as basement membrane-specific heparan sulfate proteoglycan core protein (HSPG) or heparan sulfate proteoglycan 2 (HSPG2), is a protein that in humans is encoded by the HSPG2 gene. The HSPG2 gene codes for a 4,391 amino acid protein with a molecular weight of 468,829. It is one of the largest known proteins. The name perlecan comes from its appearance as a "string of pearls" in rotary shadowed images.

<span class="mw-page-title-main">Decorin</span> Protein-coding gene in humans

Decorin is a protein that in humans is encoded by the DCN gene.

<span class="mw-page-title-main">Biglycan</span> Protein-coding gene in humans

Biglycan is a small leucine-rich repeat proteoglycan (SLRP) which is found in a variety of extracellular matrix tissues, including bone, cartilage and tendon. In humans, biglycan is encoded by the BGN gene which is located on the X chromosome.

<span class="mw-page-title-main">Syndecan 1</span> Protein which in humans is encoded by the SDC1 gene

Syndecan 1 is a protein which in humans is encoded by the SDC1 gene. The protein is a transmembrane heparan sulfate proteoglycan and is a member of the syndecan proteoglycan family. The syndecan-1 protein functions as an integral membrane protein and participates in cell proliferation, cell migration and cell-matrix interactions via its receptor for extracellular matrix proteins. Syndecan-1 is a sponge for growth factors and chemokines, with binding largely via heparan sulfate chains. The syndecans mediate cell binding, cell signaling, and cytoskeletal organization and syndecan receptors are required for internalization of the HIV-1 tat protein.

<span class="mw-page-title-main">Syndecan-2</span> Protein-coding gene in the species Homo sapiens

Syndecan-2 is a protein that in humans is encoded by the SDC2 gene.

<span class="mw-page-title-main">ADAMTS4</span> Protein-coding gene in the species Homo sapiens

A disintegrin and metalloproteinase with thrombospondin motifs 4 is an enzyme that in humans is encoded by the ADAMTS4 gene.

<span class="mw-page-title-main">MMP10</span> Protein-coding gene in the species Homo sapiens

Stromelysin-2 also known as matrix metalloproteinase-10 (MMP-10) or transin-2 is an enzyme that in humans is encoded by the MMP10 gene.

<span class="mw-page-title-main">Laminin subunit alpha-1</span> Protein-coding gene in the species Homo sapiens

Laminin subunit alpha-1 is a protein that in humans is encoded by the LAMA1 gene.

<span class="mw-page-title-main">Syndecan-3</span> Protein-coding gene in the species Homo sapiens

Syndecan-3 is a protein that in humans is encoded by the SDC3 gene.

<span class="mw-page-title-main">MMP19</span> Protein-coding gene in the species Homo sapiens

Matrix metalloproteinase-19 (MMP-19) also known as matrix metalloproteinase RASI is an enzyme that in humans is encoded by the MMP19 gene.

<span class="mw-page-title-main">HAPLN1</span> Protein-coding gene in the species Homo sapiens

Hyaluronan and proteoglycan link protein 1 is a protein that in humans is encoded by the HAPLN1 gene.

<span class="mw-page-title-main">TSG-6</span> Protein-coding gene in the species Homo sapiens

Tumor necrosis factor-inducible gene 6 protein also known as TNF-stimulated gene 6 protein or TSG-6 is a protein that in humans is encoded by the TNFAIP6 gene.

<span class="mw-page-title-main">MMP8</span> Protein-coding gene in the species Homo sapiens

Neutrophil collagenase, also known as matrix metalloproteinase-8 (MMP-8) or PMNL collagenase (MNL-CL), is a collagen cleaving enzyme which is present in the connective tissue of most mammals. In humans, the MMP-8 protein is encoded by the MMP8 gene. The gene is part of a cluster of MMP genes which localize to chromosome 11q22.3. Most MMP's are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. However, the enzyme encoded by this gene is stored in secondary granules within neutrophils and is activated by autolytic cleavage.

<span class="mw-page-title-main">CSPG5</span> Protein-coding gene in the species Homo sapiens

Chondroitin sulfate proteoglycan 5 is a protein that in humans is encoded by the CSPG5 gene.

<span class="mw-page-title-main">Link domain</span> Protein domain

A Link domain or Link module, also known as Xlink domain, is a protein domain that binds to hyaluronic acid. It is important in blood cell migration and apoptosis. The link domain is found in some extracellular proteins in vertebrates such as the hyalectans. It appears to be involved in extracellular matrix assembly and stability, cell adhesion, and migration.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000157766 - Ensembl, May 2017
  2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. 1 2 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. doi: 10.1016/S0021-9258(17)35257-2 . PMID   1985970.
  4. Aspberg A (December 2012). "The different roles of aggrecan interaction domains". The Journal of Histochemistry and Cytochemistry. 60 (12): 987–96. doi:10.1369/0022155412464376. PMC   3527881 . PMID   23019016.
  5. 1 2 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. doi:10.1103/PhysRevLett.131.138101. PMID   37832020. S2CID   263252529.
  6. Nap RJ, Szleifer I (November 2008). "Structure and interactions of aggrecans: statistical thermodynamic approach". Biophys. J. 95 (10): 4570–83. Bibcode:2008BpJ....95.4570N. doi:10.1529/biophysj.108.133801. PMC   2576360 . PMID   18689463.
  7. Hascall VC, Sajdera SW (10 October 1970). "Physical properties and polydispersity of proteoglycan from bovine nasal cartilage". The Journal of Biological Chemistry. 245 (19): 4920–30. doi: 10.1016/S0021-9258(18)62796-6 . PMID   5506265.
  8. Chandran PL, 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.
  9. 1 2 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.
  10. 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. doi: 10.22203/eCM.v011a01 . PMID   16425147.
  11. Sivan SS, Wachtel E, Roughley P (2014). "Structure, function, aging and turnover of aggrecan in the intervertebral disc". Biochim. Biophys. Acta. 1840 (10): 3181–9. doi:10.1016/j.bbagen.2014.07.013. PMID   25065289.
  12. 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): 690–3. doi:10.1016/j.biocel.2012.01.010. PMID   22297263.
  13. 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