Aggrecan
Encyclopedia
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
. 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 carbohydrate
s; the human
form of the protein is 2316 amino acid
s long and can be expressed in multiple isoforms due to alternative splicing
.
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. Along with type-II collagen
, aggrecan forms a major structural component of cartilage
, particularly articular cartilage. Aggrecan consists of two globular
structural domains at the N-terminal end and one globular domain at the C-terminal end, separated by a large domain heavily modified with glycosaminoglycan
s. The two main modifier moieties are themselves arranged into distinct regions, a chondroitin sulfate
and a keratan sulfate
region. It contains three globular domains, G1, G2, and G3 that are involved in aggregation, hyaluronan
binding, cell adhesion
, and chondrocyte
apoptosis. A large extended region (CS) between G2 and G3 for glycosaminoglycan chain attachment. G1 comprises the amino terminus of the core protein.
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 domain
s, carbohydrate recognition domains (CRD), complement binding protein (CBP)-like domains, immunoglobulin folds
and proteoglycan tandem repeats.
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.
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
. Protease
s capable of degrading aggrecans are called aggrecanase
s, and they are members of the ADAM
(A Disintegrin
And Metalloprotease) protein family.
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.
with versican
.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the ACAN gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. This gene is a member of the aggrecan/versican proteoglycan
Chondroitin sulfate proteoglycan
Chondroitin sulfate proteoglycans are proteoglycans consisting of a core protein and chondroitin sulfate. They are structural components of a variety of human tissues, for example of cartilage.The following CSPGs have been identified:...
family. The encoded protein is an integral part of the extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
in cartilagenous tissue and it withstands compression in cartilage
Cartilage
Cartilage is a flexible connective tissue found in many areas in the bodies of humans and other animals, including the joints between bones, the rib cage, the ear, the nose, the elbow, the knee, the ankle, the bronchial tubes and the intervertebral discs...
.
Aggrecan is a proteoglycan
Proteoglycan
Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan chain. The point of attachment is a Ser residue to which the glycosaminoglycan is joined through a tetrasaccharide bridge...
, or a protein modified with large carbohydrate
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...
s; the human
Human
Humans are the only living species in the Homo genus...
form of the protein is 2316 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s long and can be expressed in multiple isoforms due to alternative splicing
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
.
Structure
Aggrecan is a high molecular weight (1x106 < M < 3x106) proteoglycan. It exhibits a bottlebrush structure, in which chondroitin sulfateChondroitin sulfate
Chondroitin sulfate is a sulfated glycosaminoglycan 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...
and keratan sulfate
Keratan sulfate
Keratan sulfate , 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...
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. Along with type-II collagen
Type-II collagen
Type-II collagen is the basis for articular cartilage and hyaline cartilage.It makes up 50% of all protein in cartilage and 85-90% of collagen of articular cartilage....
, aggrecan forms a major structural component of cartilage
Cartilage
Cartilage is a flexible connective tissue found in many areas in the bodies of humans and other animals, including the joints between bones, the rib cage, the ear, the nose, the elbow, the knee, the ankle, the bronchial tubes and the intervertebral discs...
, particularly articular cartilage. Aggrecan consists of two globular
Globular protein
Globular proteins, or spheroproteins are one of the two main protein classes, comprising "globe"-like proteins that are more or less soluble in aqueous solutions...
structural domains at the N-terminal end and one globular domain at the C-terminal end, separated by a large domain heavily modified with glycosaminoglycan
Glycosaminoglycan
Glycosaminoglycans or mucopolysaccharides are long unbranched polysaccharides consisting of a repeating disaccharide unit. The repeating unit consists of a hexose or a hexuronic acid, linked to a hexosamine .-Production:Protein cores made in the rough endoplasmic reticulum are posttranslationally...
s. The two main modifier moieties are themselves arranged into distinct regions, a chondroitin sulfate
Chondroitin sulfate
Chondroitin sulfate is a sulfated glycosaminoglycan 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...
and a keratan sulfate
Keratan sulfate
Keratan sulfate , 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...
region. It contains three globular domains, G1, G2, and G3 that are involved in aggregation, hyaluronan
Hyaluronan
Hyaluronan is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues...
binding, cell adhesion
Cell adhesion
Cellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Correct cellular adhesion is essential in maintaining multicellular structure...
, and chondrocyte
Chondrocyte
Chondrocytes are the only cells found in cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans...
apoptosis. A large extended region (CS) between G2 and G3 for glycosaminoglycan chain attachment. G1 comprises the amino terminus of the core protein.
The aggrecan family includes other important members such as versican
Versican
Versican, also known as VCAN, is a large extracellular matrix proteoglycan that is present in a variety of human tissues. It is encoded by the VCAN gene....
, also named PG-M, neurocan, brevican and the cell surface HA receptor CD44
CD44
The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the CD44 gene.- Tissue distribution and isoforms :...
. They are modular proteoglycans containing combinations of structural motifs, such as EGF-like domain
EGF-like domain
EGF-like domain is an evolutionary conserved protein domain, of about thirty to forty amino-acid residues long, which was found in a large number of mostly animal proteins. All these repeats are found in the extracellular domain of membrane-bound proteins or in proteins known to be secreted...
s, carbohydrate recognition domains (CRD), complement binding protein (CBP)-like domains, immunoglobulin folds
Immunoglobulin domain
The immunoglobulin domain is a type of protein domain that consists of a 2-layer sandwich of between 7 and 9 antiparallel β-strands arranged in two β-sheets with a Greek key topology....
and proteoglycan tandem repeats.
Function
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
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
Proteolysis
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...
. Such degradation has been associated with the development of arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....
. Protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
s capable of degrading aggrecans are called aggrecanase
Aggrecanase
Aggrecanases are proteolytic enzymes that are members of the ADAM protein family. Aggrecanases act on large proteoglycans known as aggrecans, which are components of connective tissues such as cartilage. The inappropriate activity of aggrecanase is a mechanism by which cartilage degradation occurs...
s, and they are members of the ADAM
ADAM Protein
ADAM is a family of peptidase proteins. It is also known as the adamalysin family or MDC family. ADAMs are classified as sheddases because they cut off or shed extracellular portions of transmembrane proteins. For example, ADAM10 can cut off part of the HER2 receptor, activating it...
(A Disintegrin
Disintegrin
Disintegrins are a family of small proteins from viper venoms that function as potent inhibitors of both platelet aggregation and integrin-dependent cell adhesion....
And Metalloprotease) protein family.
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.
Interactions
Aggrecan has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with versican
Versican
Versican, also known as VCAN, is a large extracellular matrix proteoglycan that is present in a variety of human tissues. It is encoded by the VCAN gene....
.