Proteins Tied In Knots

Knots in the polypeptide backbone represent some of the most complicated structures seen in proteins, and their formation is not well understood. Even when knots are present in the proteins’ native state, researchers haven’t known whether those knots would persist in a denatured state. Anna L. Mallam, Joseph M. Rogers, and Sophie E. Jackson of the University of Cambridge have now found knotted conformations in two denatured bacterial proteins: the methyltransferases YibK from Haemophilus influenzae and YbeA from Escherichia coli (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.0912161107). The researchers trapped the knotted conformations by circularizing the proteins with a disulfide bond between cysteines added to both ends of each one. These circularized denatured forms refold to their correct native structures as fast as the natural protein does. The researchers’ results suggest that folding of the natural protein may also begin from a knotted state. Such knotted conformations may serve a self-chaperoning function that helps the protein avoid misfolding and aggregation in the cellular environment, the authors speculate.