ADAMTS2: More than a procollagen N-proteinase

Abstract

A disintegrin and metalloproteinase with thrombospondin motifs 2 (ADAMTS2) is a member of the ADAMTS zinc metalloproteinase family, best known for its role as a procollagen I N-proteinase in the maturation of fibrillar collagens. Biallelic defects in the ADAMTS2 gene, resulting in a loss of ADAMTS2 enzyme activity and consequent retention of N-propeptides in type I procollagen molecules, lead to the rare monogenic disease Ehlers-Danlos syndrome dermatosparaxis type (dEDS) in humans, and dermatosparaxis in animals, conditions that are hallmarked by extreme fragility of the skin and other soft connective tissues. Recent studies have expanded the substrate repertoire of ADAMTS2 considerably, revealing its potential implication in several biological processes, including angiogenesis, lymphangiogenesis, neurodevelopment, immunity, and spermatogenesis. There is also emerging evidence for a role for ADAMTS2 in complex disorders, including cancer and cardiovascular and neurodegenerative disease. These findings may not only provide answers to hitherto unsolved questions in dermatosparaxis but also unveil a therapeutic and/or biomarker potential of ADAMTS2 in many diseases. This narrative review provides an in-depth overview of the discovery, structure, regulation, and enzymatic role of ADAMTS2, its role in fibrillar collagen maturation and in dEDS pathogenesis, as well as its newly discovered substrates and its potential role in complex disorders.

Keywords: ADAMTS2; Collagen; Dermatosparaxis; Ehlers-Danlos syndrome; Procollagen N-Proteinase.

Figure 1

Clinical and ultrastructural manifestation of dermatosparaxis in different animal species. (A) A large and irregular tear in the skin of a male Drakensberger calf.(B) Deep lacerations in the neck skin of a Dorper lamb.(C) Joint swelling, atrophic scarring, and multifocal wounds on the front paw of an Alapaha blue blood bulldog.(D) Skin tear in a transgenic Adamts2^−/− mouse caused by gentle scruffing (picture courtesy of Prof. Colige). (E, F) Transmission electron microscopy image of cross section of the dermal collagen fibrils of a wild-type Dachshund and a dermatosparactic Alapaha blue blood bulldog.

Figure 2

Schematic representation of the exon (A) and protein domain (B) structure of ADAMTS2. The ADAMTS2 protein consists of an N-terminal protease domain and a C-terminal ancillary domain. The N-terminal protease domain consists of a short signal peptide, a pro-domain, and the metalloproteinase domain, containing the catalytic site (star). The larger C-terminal domain comprises the disintegrin-like domain, a singular thrombospondin type 1 motif repeat (TSR) followed by a cysteine-rich domain, a spacer domain, and three more TSRs, ending with a C-terminal procollagen N-propeptidase domain. All known pathogenic variants causing Ehlers-Danlos syndrome dermatosparaxis type (dEDS) are indicated both at the gene (NM_014244.5) and protein level. Variants indicated with superscript A and B occur as compound heterozygous; all other variants are found in homozygous state. (C) Summary of the clinical features observed in dEDS made using biorender.com.

Figure 3

The putative ADAMTS2 promotor region on which putative and confirmed transcription factor (TF) binding sites are indicated.

Figure 4

Overview of the different processes involving ADAMTS2 and their involvement in complex disorders. ADAMTS2 is involved in the organization of the extracellular matrix (ECM) through its role in the N-terminal maturation of several fibrillar collagens (type I, III and V) and lysyl oxidase (LOX) as well as through its potential substrates type XIV collagen (COL XIV), fibronectin (FN), and several small leucine-rich proteoglycans (SLRPs). It is potentially involved in transforming growth factor β (TGFβ) signaling through the proteolytic cleavage of pro-TGFβ and its receptor TGFβ-RIII. In turn, ADAMTS2 expression may be regulated by TGFβ itself. Multiple potential ADAMTS2 substrates, including the SLRPs, immunoglobulins (IGs), and several complement factors, are involved in immunity. Overexpression of ADAMTS2 in tumors implanted in nude mice results in smaller and less vascularized tumors, indicating a role for ADAMTS2 in angiogenesis, which is independent of its proteolytic activity. In lymphangiogenesis, ADAMTS2 is involved in the maturation of vascular endothelial growth factor C (VEGF-C). In neural development, ADAMTS2 can cleave and inhibit Reelin and subsequent phosphorylated Disabled-1 (Dab1-P) signaling. In spermatogenesis, ADAMTS2 cleaves Dickkopf-related protein 3 (DKK3), which in turn activates Wnt signaling. TGFβ signaling itself is important in ECM regulation and immunity, as indicated by two grey arrows. Furthermore, some potential ADAMTS2 substrates are involved in multiple processes, for example, some SLRPs are involved both in immunity and collagen fibrillogenesis, further enhancing the complexity of the role of ADAMTS2 in homeostasis and disorders. The asterisk (∗) indicates that next to neural development and spermatogenesis, Reelin and DKK3, respectively, are also involved in other processes, but these are not discussed here. This image was made using biorender.com.