Lasso Proteins-Unifying Cysteine Knots and Miniproteins

Complex lasso proteins are a recently identified class of biological compounds that are present in considerable fraction of proteins with disulfide bridges. In this work, we look at complex lasso proteins as a generalization of well-known cysteine knots and miniproteins (lasso peptides). In particular, we show that complex lasso proteins with the same crucial topological features-cysteine knots and lasso peptides-are antimicrobial proteins, which suggests that they act as a molecular plug. Based on an analysis of the stability of the lasso piercing residue, we also introduce a method to determine which lasso motif is potentially functional. Using this method, we show that the lasso motif in antimicrobial proteins, as well in that in cytokines, is functionally relevant. We also study the evolution of lasso motifs, their conservation, and the usefulness of the lasso fingerprint, which extracts all topologically non-triviality concerning covalent loops. The work is completed by the presentation of extensive statistics on complex lasso proteins to analyze, in particular, the strange propensity for "negative" piercings. We also identify 21 previously unknown complex lasso proteins with an ester and a thioester bridge.