  A number of recently discovered protein structures incorporate a rather
unexpected 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. Our analysis of the complete Protein
Data Bank reveals several new knots which, along with previously discovered
ones, can shed light on such connections. In particular, we identify the most
complex knot discovered to date in human ubiquitin hydrolase, and suggest that
its entangled topology protects it against unfolding and degradation by the
proteasome. Knots in proteins are typically preserved across species and
sometimes even across kingdoms. However, we also identify a knot which only
appears in some transcarbamylases while being absent in homologous proteins of
similar structure. The emergence of the knot is accompanied by a shift in the
enzymatic function of the protein. We suggest that the simple insertion of a
short DNA fragment into the gene may suffice to turn an unknotted into a
knotted structure in this protein.
