Perlecan

3SH4, 3SH5333915530ENSG00000142798ENSMUSG00000028763P98160Q05793NM_001291860NM_005529NM_008305NP_001278789NP_005520NP_032331Perlecan (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.1gl4: NIDOGEN-1 G2/PERLECAN IG3 COMPLEX 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. Perlecan is a large multidomain (five domains, labeled I-V) proteoglycan that binds to and cross-links many extracellular matrix (ECM) components and cell-surface molecules. Perlecan is synthesized by both vascular endothelial and smooth muscle cells and deposited in the extracellular matrix. Perlecan is highly conserved across species and the available data indicate that it has evolved from ancient ancestors by gene duplication and exon shuffling. Perlecan consists of a core protein of molecular weight 470 kDa to which three long chains (each approximately 70-100 kDa) of glycosaminoglycans (often heparan sulfate, HS, but can be chondroitin sulfate, CS) are attached. The core protein consists of five distinct structural domains. The N-terminal domain I (aa ~1-195) contains attachment sites for HS chains. Although HS chains are not required for correct folding and secretion of the protein, lack of HS or decreased sulfation can decrease perlecan's ability to interact with matrix proteins. Removal of HS chains may affect matrix organization and endothelial barrier function. Domain II comprises four repeats homologous to the ligand-binding portion of the LDL receptor with six conserved cysteine residues and a pentapeptide, DGSDE, which mediates ligand binding by the LDL receptor. Domain III has homology to the domain IVa and IVb of laminin. Domain IV consists of a series of IG modules. The C-terminal Domain V, which has homology to the G domain of the long arm of laminin, is responsible for self-assembly and may be important for basement membrane formation in vivo. Thus, perlecan core protein and HS chains could modulate matrix assembly, cell proliferation, lipoprotein binding and cell adhesion. A diagram showing the domain structure of perlecan is available here Perlecan is a key component of the vascular extracellular matrix, where it interacts with a variety of other matrix components and helps to maintain the endothelial barrier function. Perlecan is a potent inhibitor of smooth muscle cell proliferation and is thus thought to help maintain vascular homeostasis. Perlecan can also promote growth factor (e.g., FGF2) activity and thus stimulate endothelial growth and re-generation. Modifications of the heparan sulfate chains on C- and N-terminal domains are the best-studied differences in the secretory pathway of perlecan. Chondroitin sulfate can be substituted for heparan sulfate, and sulfate incorporation or the sugar composition of the chains can change. Loss of enzymes involved in the heparan sulfate synthetic pathway lead to a number of conditions. Differential heparan sulfate chain modification can occur through a number of regulatory signals. Perlecan in the growth plate of mouse long bones shows glycosylation changes in the chondrocyte progression from the resting zone to the proliferating zone. Although initially the glycosaminoglycan (GAG) chains of perlecan were thought to be exclusively heparan sulfate, chondroitin sulfate chains can be substituted during specific regulatory cues. By expressing a recombinant form of the N-terminal domain I of the protein and demonstrating that digestion of the peptide with either heparanase or chondroitinase did not lead to complete loss of the peptide's activity, it was shown that chondroitin sulfate chains can be added to human perlecan. This was in agreement with previous data showing chondroitin sulfate GAG chains attached to bovine perlecan produced by chondrocytes and that recombinant human domain I protein was glycosylated with both heparan and chondroitin sulfate chains when expressed in Chinese Hamster Ovary cells. The preferential addition of heparan sulfate or chondroitin sulfate chains to domains I and V could have an effect on the differentiation of mesenchymal tissues into cartilage, bone or any number of tissues, but the regulatory mechanism of changing from heparan sulfate to chondroitin sulfate addition are not well understood. While studying the effect of proteoglycan composition on nephritic permselectivity, it was noted that puromycin treatment of human glomerular endothelial cells (HGEC) altered the sulfation level of GAG chains on proteoglycans such as perlecan, which in turn caused a decrease in the stability of the GAG chains. The core protein mRNA levels of proteoglycans were not affected, thus the decrease in GAG chains was as a result of some other factor, which in this case turned out to be a decrease in expression of sulfate transferase enzymes, which play a key role in GAG biosynthesis. It seems that there may be some overlap in diseases stemming from loss of heparan sulfate proteoglycan expression and loss of enzymes involved in heparan sulfate biosynthesis. Cells can modify their extracellular matrix and basement membranes in response to signals or stress. Specific proteases act on the protein in the extracellular environment when cells have a reason to move or change their surroundings. Cathepsin S is a cysteine protease that moderately attenuates binding of FGF-positive cells to a perlecan-positive substrate. Cathepsin S is a potential protease that acts on the core protein of perlecan in the basement membrane or stroma.