Reflections on the evolution of the vertebrate tissue inhibitors of metalloproteinases

Abstract

Jawed vertebrates (Gnathostomes) have 4 tissue inhibitors of metalloproteinases (TIMPs), multifunctional proteins that all inhibit members of the large matrix metalloproteinase (MMP) family but differ in their other roles, including the regulation of pro-MMP activation, cell growth, apoptosis and angiogenesis, and the structure of extracellular matrices (ECMs). Molecular phylogeny analyses indicate that vertebrate TIMP genes arose from an invertebrate ancestor through 3 successive duplications, possibly including 2 whole genome duplications, during early vertebrate phylogeny. TIMPs from invertebrates also inhibit metalloproteinases, bind to pro-MMPs, and contribute to ECM structures but are not orthologs of any particular vertebrate TIMP. The most ancient vertebrate superclass, the Agnatha (jawless fish), seems to provide a snapshot of a stage in TIMP evolution preceding the third gene duplication. This review examines the structures of TIMPs from different vertebrate orders using information relating to the structural basis of their various functions. Provisional conclusions are that during their evolutionary divergence, various TIMPs lost inhibitory activity toward some metalloproteinases, specialized in effects on different pro-MMPs, and developed new interactions with discrete targets (including integrins and receptors), while recapitulating a role in ECM structure. The analysis is limited by the sparse information available regarding the functional properties of nonmammalian TIMPs.-Brew, K. Reflections on the evolution of the vertebrate tissue inhibitors of metalloproteinases.

Identification of a Tissue Inhibitor of Metalloproteinase-2: An Endogenous Inhibitor of Modori-Inducing Insoluble Metalloproteinase from Yellowtail Seriola quinqueradiata Muscle

“…These results suggest the possibility that they genetically evolved from a common ancestor although the yellowtail 18 kDa protein and other fish TIMP-2 had an Ala residue at position 6, whereas Val is the most common in mammalian TIMP-2. Moreover, yellowtail 18 kDa protein and other animal TIMP-2 sequences started with the conservative sequence, Cys-X-Cys, which is the major interaction site of TIMP with the MMP catalytic domain, coordinating to the active-site divalent catalytic zinc ion of MMP. − These data support the notion that the yellowtail 18 kDa protein belongs to the TIMP-2 family of fish species.…”

Biology of Tissue Inhibitor of Metalloproteinase 3 (TIMP3), and Its Therapeutic Implications in Cardiovascular Pathology

“…In human and mouse, TIMP3 gene is located in chromosome 10 and 22, respectively (Apte et al, 1994a,b). The TIMP3 gene (Timp3) is nested in an intron of the synapsin-3 gene (Syn3), but Timp3 and Syn3 are transcribed from different DNA strands, like most nested genes, and there is no evidence showing coordination of expression or biological function between these two genes (reviewed in Candiani et al, 2010;Brew, 2019). TIMP3 expression can be regulated at both transcriptional and posttranscriptional levels.…”

“…The N-and C-terminal domains contain 3 loops each. The 3-dimentional structure of the N-terminal TIMP3 (N-TIMP3, Cys1-Asn121) exhibits a wedge-like shape and contains an oligosaccharide/oligonucleotide binding (OB) fold (consisting of 5 β-pleated strands, sA-sE), an N-terminal and a C-terminal α-helix (hI-hII, Figure 1; Wisniewska et al, 2008;Brew and Nagase, 2010;Brew, 2019).…”

“…−12, −17, −28, and −33) and ADAMTS (−1, −2, −4, and −5) (Brew and Nagase, 2010;Moore et al, 2012;Jackson et al, 2017;Brew, 2019). ADAM17 is inhibited by TIMP3 when present as a dimer; and the N-terminal domain of TIMP4 can interact with and inhibit ADAM17 in vitro, suggesting that the C-terminal domain of TIMP4 may disrupt this interaction in vivo (Amour et al, 1998;Lee et al, 2005;Brew and Nagase, 2010).…”

The Effect of Immunosuppressive Drugs on MMPs Activity in The Walls of Blood Vessels - A Systematic Review

“…Due to C-end domain they connect with metalloproteinases in 1:1 ratio. This inhibition form is a reversible process 26 , 30 - 33 . Metalloproteinases activation may be also controlled in the gene transcription stage, zymogenes release and proenzymes activation.…”