Intricate knots in proteins: Function and evolution

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.

Figure 1. Examples of the Three Different Types of Knots Found in Proteins

Colors change continuously from red (first residue) to blue (last residue). A reduced representation of the structure, based on the algorithm described in [1,6,36], is shown in the lower row. (Left) The trefoil knot (3₁) in the YBEA methyltransferase from E. coli (pdb code 1ns5; unpublished data) reveals three essential crossings in a projection onto a plane. (Middle) The figure-eight knot (4₁) in the Class II ketol-acid reductoisomerase from Spinacia oleracea (pdb code 1yve [26]) features four crossings. (Only the knotted section of the protein is shown.) (Right) The knot 5₂ in ubiquitin hydrolase UCH-L3 (pdb code 1xd3 [18]) reveals five crossings. Pictures were generated with Visual Molecular Dynamics (http://www.ks.uiuc.edu/Research/vmd) [43].

Figure 2. Structures of Transcarbamylase from X. campestris with a Trefoil Knot and from Human without a Knot

(Left) Knotted section (residues 171–278) of N-acetylornithine transcarbamylase from X. campestris with reaction product N-acetylcitrulline (pdb code 1yh1 [17]) and interacting side chains. (Right) Corresponding (unknotted) section (residues 189–286) in human ornithine transcarbamylase (pdb code 1c9y [31]) with inhibitor L-norvaline and carbamyl phosphate. Colors change continuously from red (first residue in the section) to blue (last residue in the section). The two proteins have an overall sequence identity of 29% [41]. Pictures were generated with VMD [43].