11 nots - 1 Lecture 11 Notes October 20, 2008 Perlecan and...

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1 Lecture 11 Notes October 20, 2008 Perlecan and chondrodysplasia Small Leucine Rich Proteoglycans (SLRPs): Decorin and collagen fibrillogenesis Verbatim for the cited literature with minor modifications to highlight some points Perlecan Costell et al (1999) Perlecan maintains the integrity of cartilage and some basement membranes Journal Cell Biology 147: 1109-1122. Schwartz and Domowicz.2002. Glycobiology 12: 57R-68R Perlecan: chondrodysplasia (heritable disorders of the skeleton) and basal laminae/basement membranes stability Perlecan is most often cited as a major universal component of the basal laminae. However, this large HSPG is also expressed in embryonic interstitial tissues and stroma in pathologic conditions. Modular organization of perlecan The core protein of perlecan, 467 KDa (human), is composed of five domains. The amino-terminal domain I contains three heparan sulfate (HS) chains; domain II has four LDL receptor-like repeats; domain III contains repeats resembling those in the short arm of laminin; domain IV has Ig-like repeats similar to those in NCAM, and domain V contains repeats similar to those in laminin A chain and EGF motifs. (Slides # 6-11). You do not need to memorize the order of the individual motif. As the course progresses, it will become obvious that some of these motifs are found in many ECM molecules. Molecular interactions of Perlecan (Slide 10) Perlecan binds a number of ECM molecules, cell surface receptors, and growth factors, suggesting that perlecan act as a glue to stabilize matrix organization and cell-matrix interaction and to modulate growth factor signaling for cell proliferation and differentiation. Perlecan has been shown to bind basal laminae proteins including laminin, collagen IV, and nidogen/entactin. It also binds other extracellular matrix including fibulin and fibronectin. Binding domains of perlecan for these interactions have been identified using recombinant proteins. Domain V interacts with cell surface receptors such as integrin β 1 and α -dystroglycan. Many growth factors such as fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) bind the heparan sulfate chains and the protein core of perlecan. It has been shown that perlecan is a low affinity binding molecule for β -FGF and promotes mitogenesis and angiogenesis. Perlecan and kidney filtration (Slide 12) There are several HSPG molecules in the basement membrane other than perlecan which have been best characterized, namely, agrin and smaller HSPGs. In addition to
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2 HSPGs, bamacan, a chondroitin sulfate proteoglycan, is known to be another anionic component of the basement membrane (Slide #4). The focus of the lecture is on perlecan. In a previous lecture, we examined how a developmental switch in the alpha chain composition of type IV collagen is critical for normal kidney function. The glomerular basement membrane serves as not only a tissue boundary on which cells attach but also a filter with selective permeability or a highly specialized substrate for
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11 nots - 1 Lecture 11 Notes October 20, 2008 Perlecan and...

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