Characterising the Folding Pathways of Topologically Knotted Proteins

Since 2000, when they were first identified by Willie Taylor, the number of knotted proteins within the protein database has increased and there are now nearly 300 such structures. The polypeptide chains of these proteins form topologically knotted structures. There are now examples of proteins which form simple 31 trefoil knots, 41, 52 Gordian knots and 61 Stevedore knots. Knotted proteins represent a significant challenge to both the experimental and computational protein folding communities - when and how the polypeptide chains knot during the folding of the proteins poses an additional complexity to the folding landscape. This review describes the experimental and computational studies of the structure, folding and function of naturally occurring knotted proteins including the 31 -trefoil knotted methyltransferases and 52 -knotted ubiquitin C-terminal hydrolases, as well as other systems, in addition to the recently designed trefoil-knotted protein based on the HP0242 dimer.