Leucine-rich Proteoglycan

 Biglycan, decorin, fibromodulin, lumican, PG-Lb, keratocan and mimecan are members of the family of small leucine-rich proteoglycans (SLRPs). They all have core proteins with the leucine-rich repeats (LRR) which usually occupy more than 70% of the core proteins (Figure 1). These proteoglycans are secreted from the cells after synthesis and found in the extracelluar matrix. The LRR are also found in various other molecules and, therefore, SLRPs form the LRP superfamily with the other LRR-containing molecules. The LRR domain of the SLRPs is flanked by cysteine-rich clusters which may form disulfide bonds. There are four cysteine residues at the amino terminal region and two cysteine residues at the carboxyl terminal side. The LRR motif is characterized by an xLxxLxLxxN±xaxx±a±±±±a±±a±±x±± sequence proposed by Kobe and Deisenhofer (1), where x is any amino acid, L is often a leucine (or isoleucine), N is generally asparagine but can be substituted with a cysteine or threonine, is an amino acid that may or may not be present at this position, and a is an aliphatic amino acid. Some reports consider the sequence LxxLxLxxNxL/I as a consensus sequence for the LRR motif. The crystal structure of the LRR-containing porcine ribonuclease inhibitor (RI) revealed that 15 individual LRRs adopt a stacked beta-sheet /alpha-helix hairpin structure, resulting in an overall horseshoe shape (2). The characteristics of each member proteoglycan are as follows.

Biglycan contains two chains of chondroitin sulfate (CS) or dermatan sulfate (DS) on a 38 kDa core protein. The chondroitin sulfate-containing form is commonly isolated from fetal or young bones, while the dermatan sulfate-containing form is isolated from articular cartilage. Biglycan is found associated with the cell surface or pericellular matrix of a variety of cells including specific subsets of developing mesenchymal (skeletal muscle, bone and cartilage), endothelial (blood vessels) and epithelial (keratinocytes) cells. They are also called PG-1, PG-I, DS-PGI, and PG-S1.

Decorin contains one CS or DS chain on the 36 kDa core protein. The chondroitin 4-sulfate-containing molecule is isolated from the developing bones, while the DS chain-containing molecule is usually found in articular cartilage or tendon. Decorin is relatively abundant in bone, tendon, sclera, skin, aorta and cornea. Other names for decorin include PG-2, PG-II, PG-S2, PG-40, and DS/CS-PGII. In vitro experiments have shown that decorin modifies the kinetics of collagen fibril formation and affects the morphology of collagen fibrils, and, interestingly, that it can bind TGF-beta and be involved in metabolic regulation of various cell functions.

Fibromodulin is a keratan sulfate proteoglycan present in many types of connective tissues, e.g. cartilage, tendon and skin. The core protein consists of 357 amino acid residues (42 kDa). Fibromodulin binds to type I and II collagen and affects collagen fibrillogenesis in vitro.

Lumican contains keratan sulfate chains and is expressed in a number of connective tissues including cornea, muscle, intestine and cartilage. The lumican core protein consists of 338 amino acid residues (37 kDa). Lumican in cornea has highly sulfated keratan sulfate chains and may play an important role in the acquisition and maintenance of corneal transparency. However, lumican in other tissues is found as poorly sulfated or non-sulfated glycoproteins. Lumican was so named for its role in the transparency of cornea.

PG-Lb is a CS/DS proteoglycan first isolated from embryonic chick limb cartilage (3). Recently, occurrence in mouse has been shown by the cDNA cloning and northern analysis. Epiphycan and DSPG3 have been found to be the bovine and human equivalents of PG-Lb, respectively. Different from other SLRPs, PG-Lb is expressed exclusively in the zones of flattened chondrocytes of limb cartilage. Recently, DSPG3 has been found in ligament and placental tissues as well as in cartilage.

Keratocan is so named because it contains keratan sulfate chains. Its distribution is rather limited compared with those of the other keratan sulfate-containing lumican or fibromodulin. It is abundant in cornea and sclera but much less in skin, ligament and cartilage. Like lumican, keratocan in cornea is found to contain long keratan sulfate chains, but it is present in non-corneal tissues primarily as a non-sulfated glycoprotein.

Osteoglycin is one member of the LRP superfamily. It has recently been shown that this molecule exists in bovine cornea as a keratan sulfate proteoglycan and is named mimecan.
FigureFigure Legend
Molecular organization of small leucine-rich proteoglycans.
The core proteins don't represent their actual sizes, neither the illustrated sites of glycosylation and LRR represented their actual locations.

Yukiko Mochizuki, Tamayuki Shinomura, Koji Kimata
(Aichi Medical University, Institute for Molecular Science of Medicine)
References(1) Kobe, B, Deisenhofer, J. Trends Biochem, Sci. 19, 415-421, 1994
(2) Kobe, B, Deisenhofer, J. Nature 366, 751-756, 1993
(3) Shinomura, T, Kimata, K, Oike, Y, Noro, A, Hirose, N, Tanabe, K, Suzuki, S. J. Biol. Chem. 258, 9314-9322, 1983
Mar. 15, 1998

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