Hyalectanase Activities by the ADAMTS Metalloproteases

Abstract

The hyalectan family is composed of the proteoglycans aggrecan, versican, brevican and neurocan. Hyalectans, also known as lecticans, are components of the extracellular matrix of different tissues and play essential roles in key biological processes including skeletal development, and they are related to the correct maintenance of the vascular and central nervous system. For instance, hyalectans participate in the organization of structures such as perineural nets and in the regulation of neurite outgrowth or brain recovery following a traumatic injury. The ADAMTS (A Disintegrin and Metalloprotease domains, with thrombospondin motifs) family consists of 19 secreted metalloproteases. These enzymes also perform important roles in the structural organization and function of the extracellular matrix through interactions with other matrix components or as a consequence of their catalytic activity. In this regard, some of their preferred substrates are the hyalectans. In fact, ADAMTSs cleave hyalectans not only as a mechanism for clearance or turnover of proteoglycans but also to generate bioactive fragments which display specific functions. In this article we review some of the physiological and pathological effects derived from cleavages of hyalectans mediated by ADAMTSs.

Keywords: ADAMTS; aggrecan; brevican; extracellular matrix; hyalectan; lectican; neurocan; proteoglycan; versican.

Figure 3

Schematic representation of an arthritic knee and aggrecan. G1, G2 and G3 indicate globular domains. Cleavage at the E373-A374 bond by the ADAMTSs in the interglobular domain (IGD) between G1 and G2 domains is indicated. This position is related to the development of juvenile joint diseases, causing inflammation in parts of the body like the knee. GAGs indicates glycosaminoglycans. (This position corresponds to the E392-A374 bond in reference [48]). Relative positions of additional cleavages sites (1,2,3,4) within the chondroitin sulphate-rich region are also indicated. These positions correspond to the E1279-G1280, E1467-L1468, E1572-A1573 and E1672-L1673 bonds identified in mouse cartilage aggrecan as shown in reference [72]. Main cleavage site by MMPs (N341-F342) in the IGD domain is also indicated. (This position corresponds to the N360-F361 bond in reference [48]).

Figure 1

Schematic depiction of the structure of some representative proteoglycans. The complex domain organizations of an intracellular (serglycin), a cell surface-anchored (phosphacan), a pericellular (collagen type XVIII) and an extracellular (aggrecan) proteoglycan are shown. (HEP, heparin; D1 and D2, tyrosine phosphatase; FN, fibronectin-type III repeat; CAH, catabolic anhydrase domain; CS, chondroitin sulphate chains; F, frizzled domain; TSR, thrombospondin-like 1 domain; HS, heparan sulphate proteoglycans; Col. Domain, collagen domains; TD, trimerization domain; E, endostatin domain; G1, G2 and G3, globular domains; GAGs, glycosaminoglycans).

Figure 2

The ADAMTS family of metalloproteases. Top, schematic representation of the structure of the ADAMTS metalloproteases. TSR, thrombospondin type I motif. MuPr, mucin/proteoglycan domain. GON-1, CUB and PLAC domains (“n”, number of repetitions of the indicated domain). Bottom, representative members of the ADAMTS family from each of the functional subgroups: procollagen N-propeptidase, aggrecanases/hyalectanases, COMP proteinases, vWFCP and ADAMTSs (A Disintegrin and Metalloprotease domains, with thrombospondin motifs) related to microfibril function. For detailed information about the molecular architecture of the ADAMTS metalloproteases see reference [28].

Figure 4

Schematic representation of the different isoforms of versican V0, V1, V2, V3 and V4. GAG-α and GAG-β are the two different glycosaminoglycans binding sites between the G1 and G3 globular domains. Arrows indicate some cleavage sites in versican. E405-Q406 is cleavage site in the GAG-α both in versican V0 and V2. E1428-Q1429 in versican V0 is the equivalent to E441-A442 in human versican V1 (see reference [20]).

Figure 5

Representation of brevican structures. Brevican is expressed in brain and a GPI-anchored isoform lacking G3 domain has been identified. GAGs, glycosaminoglycans. Arrows indicate the main cleavage site by ADAMTS-4. Other cleavage sites are indicated in the text.

Figure 6

Schematic representation of neurocan proteolysis. Neurocan is cleaved at M638-L639 to generate two fragments, neurocan 130 and neurocan-C, corresponding to the NH₂-terminal and COOH-terminal ends of the original undigested neurocan. G1 and G3 indicate globular domains. Other cleavage sites are indicated in the text.