A disintegrin and metalloproteinase with thrombospondin motifs 4 is an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...

that in humans is encoded by the ''ADAMTS4''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. This gene encodes a member of the

ADAMTS ADAMTS (short for a disintegrin and metalloproteinase with thrombospondin motifs) is a family of multidomain extracellular protease enzymes. 19 members of this family have been identified in humans, the first of which, ADAMTS1, was described in 19 ...

(a disintegrin and metalloproteinase with thrombospondin motifs) protein family. Members of the family share several distinct protein modules, including a propeptide region, a

metalloproteinase A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example is ADAM12 which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myoge ...

domain, a disintegrin-like domain, and a

thrombospondin Thrombospondins (TSPs) are a family of secreted glycoproteins with antiangiogenic functions. Due to their dynamic role within the extracellular matrix they are considered matricellular proteins. The first member of the family, thrombospondin 1 (T ...

type 1 (TS) motif. Individual members of this family differ in the number of

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

TS motifs, and some have unique C-terminal domains. The

encoded by this gene lacks a C-terminal TS motif. It can degrade

aggrecan 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. This gene is a member of the lectican ( chondroitin sulfate pro ...

, a major proteoglycan of cartilage,

brevican Brevican core protein is a protein that in humans is encoded by the ''BCAN'' gene. Brevican is a member of the lectican protein family. Brevican is localised to the surface of neurons in the brain. In melanocytic cells, BCAN gene expression may ...

, a brain-specific

extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide struc ...

protein, neurocan and

versican Versican is a large extracellular matrix proteoglycan that is present in a variety of human tissues. It is encoded by the ''VCAN'' gene. Versican is a large chondroitin sulfate proteoglycan with an apparent molecular mass of more than 1000kDa. ...

. The cleavage of aggrecan and brevican suggests key roles of this enzyme in arthritic disease and in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

, potentially, in the progression of

glioma A glioma is a type of tumor that starts in the glial cells of the brain or the spine. Gliomas comprise about 30 percent of all brain tumors and central nervous system tumours, and 80 percent of all malignant brain tumours. Signs and symptoms ...

Structure

ADAMTS4 is the shortest known

, lacking the C-terminal domain and is the only non-glycosylated

. It also only has one

type 1 motif (TSR), whereas all the other ADAMTS have two or more TSRs. The TSR is important for binding of the enzyme to the

and hence its substrate specificity. Adjacent to the C-terminal TSR is a disintegrin-like domain, a

cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, s ...

-rich region that stacks against the active-site of the

when in its final folded tertiary structure.

Function

ADAMTS4 is capable of cleaving all the large

chondroitin sulfate Chondroitin sulfate is a sulfated glycosaminoglycan (GAG) composed of a chain of alternating sugars ( N-acetylgalactosamine and glucuronic acid). It is usually found attached to proteins as part of a proteoglycan. A chondroitin chain can have over ...

hyaluronan Hyaluronic acid (; abbreviated HA; conjugate base hyaluronate), also called hyaluronan, is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. It is unique among glycosaminogl ...

-binding

proteoglycan Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan (GAG) chain(s). The point of attachment is a serine (Ser) residue to w ...

s (CSPGs), including

, neurocan and

. Like ADAMTS5, it can be effectively inhibited by tissue inhibitor of

-3 (

TIMP3 Metalloproteinase inhibitor 3 is a protein that in humans is encoded by the ''TIMP3'' gene. This gene belongs to the tissue inhibitor of metalloproteinases gene family. The proteins encoded by this gene family are inhibitors of the matrix metall ...

) and this inhibition can be enhanced in the presence of

. In addition to

, it can also be inhibited by calcium pentosan polysulfate. ADAMTS4 is expressed in

ovary The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the bod ...

spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the spin ...

adrenal cortex The adrenal cortex is the outer region and also the largest part of an adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. It ...

ciliary ganglion The ciliary ganglion is a bundle of nerve parasympathetic ganglion located just behind the eye in the posterior orbit. It is 1–2 mm in diameter and in humans contains approximately 2,500 neurons. The ganglion contains postganglionic parasympat ...

trigeminal ganglion A trigeminal ganglion (or Gasserian ganglion, or semilunar ganglion, or Gasser's ganglion) is the sensory ganglion at the base of each of the two trigeminal nerves (CN V), occupying a cavity ( Meckel's cave) in the dura mater, covering the trigem ...

brain The brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head ( cephalization), usually near organs for special ...

retina The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...

pancreas The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an en ...

(islets), fetal lung,

breast The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues. In females, it serves as the mammary gland, which produces and s ...

myoepithelial cells,

tendon A tendon or sinew is a tough, high-tensile-strength band of dense fibrous connective tissue that connects muscle to bone. It is able to transmit the mechanical forces of muscle contraction to the skeletal system without sacrificing its ability ...

and cartilage.

Clinical Significance

ADAMTS4 (and ADAMTS5) are the major proteinases responsible for the degradation of

s in

articular cartilage Hyaline cartilage is the glass-like (hyaline) and translucent cartilage found on many joint surfaces. It is also most commonly found in the ribs, nose, larynx, and trachea. Hyaline cartilage is pearl-gray in color, with a firm consistency and h ...

osteoarthritis Osteoarthritis (OA) is a type of degenerative joint disease that results from breakdown of joint cartilage and underlying bone which affects 1 in 7 adults in the United States. It is believed to be the fourth leading cause of disability in the ...

. Which of these aggrecanases is more important in cartilage degradation appears to be species-specific, with ADAMTS4 more important in human disease (but ADAMTS5 more important in

mouse A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...

models of

Alternative names

*Aggrecanase-1 (initial name reflecting its ability to cleave

)

References

External links

* The

MEROPS MEROPS is an online database for peptidases (also known as proteases, proteinases and proteolytic enzymes) and their inhibitors. The classification scheme for peptidases was published by Rawlings & Barrett in 1993, and that for protein inhibi ...