Perlecan
From Wikipedia, the free encyclopedia
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Heparan sulfate proteoglycan 2
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| PDB rendering based on 1gl4. | |||||||||||
| Available structures: 1gl4 | |||||||||||
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| Symbol(s) | HSPG2; PLC; PRCAN; SJA; SJS; SJS1 | ||||||||||
| External IDs | OMIM: 142461 HomoloGene: 68473 | ||||||||||
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| Orthologs | |||||||||||
| Human | Mouse | ||||||||||
| Entrez | 3339 | n/a | |||||||||
| Ensembl | ENSG00000142798 | n/a | |||||||||
| Uniprot | P98160 | n/a | |||||||||
| Refseq | NM_005529 (mRNA) NP_005520 (protein) |
n/a (mRNA) n/a (protein) |
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| Location | Chr 1: 22.02 - 22.14 Mb | n/a | |||||||||
| Pubmed search | [1] | n/a | |||||||||
Heparan sulfate proteoglycan 2 (HSPG2), is a human gene which encodes the perlecan protein.[1]
Perlecan is a large multidomain proteoglycan that binds to and cross-links many extracellular matrix (ECM) components and cell-surface molecules.[2] 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.
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[edit] Structure
Perlecan consists of a core protein of molecular weight 450 kDa to which three long chains (each approximately 70-100 kDa) of glycosaminoglycans (often heparan sulfate, HS) 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 ability to interact with matrix proteins. Removal of HS chains thus, 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 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
[edit] Function
Perlecan is a key component of the vascular extracellular matrix, here 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.
[edit] Disease association
[edit] Development
The importance of perlecan to mammalian development is demonstrated by perlecan gene knockout experiments. Nearly half of all mice in which the perlecan gene has been knocked out (perlecan null mice) die at embryonic day 10.5, when the perlecan gene normally starts to be expressed.[3] Others die just after birth with severe defects such as abnormal basement membrane formation, defective cephalic and long bone development and achondroplasia.[4][5]
Studies from gene knockout mice and human diseases have also revealed critical in vivo roles for perlecan in cartilage development[6] and neuromuscular junction activity.[7]
[edit] Cancer
While Perlecan suppression causes substantial inhibition of tumor growth and neovascularization in null mice, in contrast, when perlecan-null cells are injected into nude mice enhanced tumor growth is observed when compared to controls.
[edit] Diabetes and cardiovascular disease
Perlecan levels are decreased in many disease states - e.g., diabetes, atherosclerosis and arthritis. Perlecan has an important role in the maintenance of the glomerular filtration barrier.[8] Decreased perlecan in the glomerular basement membrane has a central role in the development of diabetic albuminuria. Perlecan expression is down regulated by many atherogenic stimuli and thus Perlecan is thought to play a protective role in atherosclerosis.[9][10]
[edit] References
- ^ Entrez Gene: HSPG2 heparan sulfate proteoglycan 2.
- ^ Iozzo RV (1994). "Perlecan: a gem of a proteoglycan". Matrix Biol. 14 (3): 203–8. doi:. PMID 7921536.
- ^ Girós A, Morante J, Gil-Sanz C, Fairén A, Costell M (2007). "Perlecan controls neurogenesis in the developing telencephalon". BMC Dev. Biol. 7: 29. doi:. PMID 17411441.
- ^ Arikawa-Hirasawa E, Watanabe H, Takami H, Hassell JR, Yamada Y (1999). "Perlecan is essential for cartilage and cephalic development". Nat. Genet. 23 (3): 354–8. doi:. PMID 10545953.
- ^ Costell M, Gustafsson E, Aszódi A, Mörgelin M, Bloch W, Hunziker E, Addicks K, Timpl R, Fässler R (1999). "Perlecan maintains the integrity of cartilage and some basement membranes". J. Cell Biol. 147 (5): 1109–22. doi:. PMID 10579729.
- ^ Gomes RR, Farach-Carson MC, Carson DD (2004). "Perlecan functions in chondrogenesis: insights from in vitro and in vivo models". Cells Tissues Organs (Print) 176 (1-3): 79–86. doi:. PMID 14745237.
- ^ Hassell J, Yamada Y, Arikawa-Hirasawa E (2002). "Role of perlecan in skeletal development and diseases". Glycoconj. J. 19 (4-5): 263–7. doi:. PMID 12975604.
- ^ Conde-Knape K (2001). "Heparan sulfate proteoglycans in experimental models of diabetes: a role for perlecan in diabetes complications". Diabetes Metab. Res. Rev. 17 (6): 412–21. doi:. PMID 11757076.
- ^ Pillarisetti S (2000). "Lipoprotein modulation of subendothelial heparan sulfate proteoglycans (perlecan) and atherogenicity". Trends Cardiovasc. Med. 10 (2): 60–5. doi:. PMID 11150731.
- ^ Segev A, Nili N, Strauss BH (2004). "The role of perlecan in arterial injury and angiogenesis". Cardiovasc. Res. 63 (4): 603–10. doi:. PMID 15306215.
