Intricate Knots in Proteins: Function and Evolution

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Abstract
Our investigation of knotted structures in the Protein Data Bank reveals the most complicated knot discovered to date. We suggest that the occurrence of this knot in a human ubiquitin hydrolase might be related to the role of the enzyme in protein degradation. While knots are usually preserved among homologues, we also identify an exception in a transcarbamylase. This allows us to exemplify the function of knots in proteins and to suggest how they may have been created. Several protein structures incorporate a rather unusual structural feature: a knot in the polypeptide backbone. These knots are extremely rare, but their occurrence is likely connected to protein function in as yet unexplored fashion. The authors' analysis of the complete Protein Data Bank reveals several new knots that, along with previously discovered ones, may shed light on such connections. In particular, they identify the most complex knot discovered to date in a human protein, and suggest that its entangled topology protects it against unfolding and degradation. Knots in proteins are typically preserved across species and sometimes even across kingdoms. However, there is also one example of a knot in a protein that is not present in a closely related structure. The emergence of this particular knot is accompanied by a shift in the enzymatic function of the protein. It is suggested that the simple insertion of a short DNA fragment into the gene may suffice to cause this alteration of structure and function.