The Repertoire of Tissue Inhibitors of Metalloproteases: Evolution, Regulation of Extracellular Matrix Proteolysis, Engineering and Therapeutic Challenges

Abstract

Tissue inhibitors of metalloproteases (TIMPs) belong to a fascinating protein family expressed in all Metazoa. They act as regulators of the turnover of the extracellular matrix, and they are consistently involved in essential processes. Herein, we recapitulate the main activities of mammalian TIMPs (TIMP1-4) in the control of extracellular-matrix degradation and pathologies associated with aberrant proteostasis. We delineate the activity of TIMPs in the control of extracellular matrix (ECM) homeostasis and discuss the diversity of TIMPs across metazoans taking into account the emergence of the components of the ECM during evolution. Thus, the TIMP repertoire herein analysed includes the homologues from cnidarians, which are coeval with the origins of ECM components; protostomes (molluscs, arthropods and nematodes); and deuterostomes (echinoderms and vertebrates). Several questions, including the maintenance of the structure despite low sequence similarity and the strategies for TIMP engineering, shed light on the possibility to use recombinant TIMPs integrating unique features and binding selectivity for therapeutic applications in the treatment of inflammatory pathologies.

Keywords: ECM; TIMP diversity; TIMPs; cancer; inflammation; protein engineering; protein evolution.

Figure 1

Eumetazoa phylogeny. The diagram represents the relationships among taxa; the branch lengths do not account for evolutionary distances among species. The main taxonomic divisions are indicated as well as the appearance of the ECM toolkit along with its evolution [10].

Figure 2

NJ phylogenetic tree based on the TIMPs from cnidarians to vertebrates. The tree was generated using MEGA X. All the sequences used were obtained from GenBank at National Centre for Biotechnology Information (NCBI). The p-distance model was used to construct the phylogenetic tree. Internal branches were assessed using 1000 bootstrap replications. Bootstrap values greater than 40% are indicated at the nodes. Gene nomenclature is according to [10]. The main taxonomic divisions are indicated. Single- and double-domain TIMPs are shown next to the corresponding groups Different colors represent TIMPs clustering according to isoforms in vertebrates.