Perlecan: how does one molecule do so many things?

Abstract

Perlecan is a large multi-domain extracellular matrix proteoglycan that plays a crucial role in tissue development and organogenesis. In vertebrates, perlecan functions in a diverse range of developmental and biological processes, from the establishment of cartilage to the regulation of wound healing. How can a single molecule modulate such a wide variety of processes? We suggest that perlecan employs the same basic mechanism, based on interactions with growth factors, morphogens and matrix proteins, to regulate each of these processes and that the local extracellular environment determines the function of perlecan and consequently its downstream effects on the structure and function of the organ. We discuss this hypothesis in relation to its role in three major vertebrate developmental processes: angiogenesis, chondrogenesis and endochondral ossification.

Application of drug discovery software to the identification of heparin-binding sites on protein surfaces: a computational survey of the 4-helix cytokines

“…2 Residues containing atoms within 3.5 Å of ligand in the 5 lowest energy complexes ... [1] ... [3] Page 17 of 34 http://mc.manuscriptcentral.com/tandf/jenmol 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 2 Residues containing atoms within 3.5 Å of ligand in the 5 lowest energy complexes Table 3: Prediction of heparin binding to the interferon/IL10 group of 4-helical cytokines. ... [7] ... [19] ... [15] ... [20] ... [18] ... [17] ... [21] ... [5] ... [22] ... [6] ... [16] ... [13] ... [24] ... [8] ... [25] ... [23] ... [14] ... [26] ... [9] ... [27] ... …”

“…It is a particularly highly sulfated example of the class of glycosaminoglycans (GAGs) known as heparan sulfate [2], and is found in mast cell granules, where it is essential for the correct storage of proteases [3,4]. Heparan sulfate (HS) is present, as the glycan side-chain of several proteoglycans, on the surfaces of most cells [2] and in the extracellular matrix [5], where it interacts with, and modulates the actions of, many of the cytokines, chemokines, growth factors, and other proteins which exert their effects in inflammation [6], reproduction [7], the immune system, and embryonic differentiation and development [8]. Sequence and structure in heparin and heparan sulfate…”

Recent advances in annular pathobiology provide insights into rim-lesion mediated intervertebral disc degeneration and potential new approaches to annular repair strategies

“…Perlecan is a, large, modular, multifunctional proteoglycan with a 467-kDa protein core containing five distinct domains with homology to the laminin A chain, low density lipoprotein receptor, neural cell adhesion molecule and epidermal growth factor [62,94,102]. In man, domain-I in perlecan is the main region of GAG substitution [19,62,94,102] while domain V may also have an additional two HS attachment sites [54,65]. When substituted with HS, perlecan domain-1 promotes binding to laminin-1 and collagen IV and can also act as a low affinity co-receptor for FGF-1, 2, 7, 9 and 18 while domains III and V act as a receptor for FGF-7 [63][64][65].…”

“…In man, domain-I in perlecan is the main region of GAG substitution [19,62,94,102] while domain V may also have an additional two HS attachment sites [54,65]. When substituted with HS, perlecan domain-1 promotes binding to laminin-1 and collagen IV and can also act as a low affinity co-receptor for FGF-1, 2, 7, 9 and 18 while domains III and V act as a receptor for FGF-7 [63][64][65]. The low density lipoprotein (LDL) repeats in perlecan domain II bind connective tissue growth factor (CTGF) [2,101], CTGF modulates bone morphogenetic protein (BMP) and transforming growth factor (TGF)-b signalling to co-ordinate morphogenesis, and chondrogenic and angiogenic events during skeletal development [2,101].…”

Integrin α2β1 Is the Required Receptor for Endorepellin Angiostatic Activity

“…Accordingly, much attention has been invested in the search for and characterization of anti-angiogenic agents to enable regulated and inhibited tumor angiogenesis as part of cancer therapies (1). The proteoglycan perlecan plays a key role in the angiogenic process, primarily by modulating the availability and activity of growth factors involved in angiogenesis such as fibroblast growth factor 2, VEGF, 3 and platelet-derived growth factor (2)(3)(4)(5)(6). The most C-terminal part of perlecan (domain V), named endorepellin, is a powerful angiogenic inhibitor (7).…”