Proteolytic enzymes are the enzymes that break down protein, for example, during digestion and tissue remodelling. In order to control their destructive potential, the enzymes are ‘muted’ under certain circumstances by protein inhibitors, which can be small molecules jamming the proteases’ jaws – or large complexes that act like cages or traps.
By F. Xavier Gomis-Rüth
Proteolytic enzymes cleave peptides and proteins as part of normal physiological and pathological processes. This cleavage is essentially irreversible, so that it must be very tightly regulated to prevent aberrant reactions. Failure in this regulation can have severe consequences such as tissue destruction, neurological disorders, cardiovascular diseases, diabetes and cancer.
The work reviewed in the review paper published in the journal Biological Chemistry, unveils the mechanistic details of the inhibitory function of α2Ms at the molecular level. One regulatory mechanism is provided by protein inhibitors which tightly bind to, and block their target enzymes. One such family of inhibitors are the α2-macroglobulins (α2Ms).
Venus flytrap mechanisms are employed
These are very large proteins made up of several domains that are mainly found in the blood plasma of vertebrates and have a broad spectrum of inhibitory capacities (as defense against infections, among other things). α2Ms employ irreversible trap mechanisms resulting from large structural rearrangement upon cleavage in a trigger ‘bait region’ through the target proteolytic enzyme.
After decades of research, structural details of these mechanisms have begun to emerge for multimeric and monomeric α2Ms, which use “Venus-flytrap” and “snap-trap” mechanisms, respectively. In the first case, inhibition occurs through physical entrapment in a large cage in which enzymes are still active against small substrates and inhibitors that can diffuse through the cage bars. In the second case, covalent binding and physical hindrance of the enzyme inhibit its activity against very large substrates.
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Theodoros Goulas, Irene Garcia-Ferrer, Aniebrys Marrero, Laura Marino-Puertas, Stephane Duquerroy, F. Xavier Gomis-Rüth: Structural and functional insight into pan-endopeptidase inhibition by α2-macroglobulins. 24.06.2017