Reflections on the evolution of the vertebrate tissue inhibitors of metalloproteinases

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. FASEB J. 33, 71–87 (2019). www.fasebj.org