Topological twists in nature: Proteins with a pierced lasso topology

The correlation between structural motifs and their 3D-structure has previously been established to influence biology. However, less is known about the biological implications of protein topology, i.e., motifs that can act as a structural switch in response to environmental changes. To answer biological questions regarding proteins subject to topological constraints that can be controlled by the chemical environment, we study proteins with a pierced lasso topology (PLT) involved in cell regulation, growth, and cell migration. PLTs are threaded “knot-like” topologies, where part of the chain pierces through a covalent loop. Interestingly, PLTs exist in 18% of all disulfide-containing proteins found in all kingdoms of life. PLTs can further be divided into 14 different classes according to their mechanism of action. They are mainly found in the extracellular matrix and organelles with an oxidizing environment. This discovery of PLTs emphasizes the topological importance of loops and links for biological activity, adding a new putative role of disulfides in proteins. Despite this large number, a connection between topology and biological function has not yet been determined. Our results show that the threaded topology initiates conformational dynamics affecting protein-protein interaction and biological function controlled by the chemical environment. Therefore, we associate the threaded disulfide-linked topology with biological function. Furthermore, we hypothesize that the introduction of PLTs in proteins may not be a stochastic event in evolution but represent a new role of disulfides in vivo.