Characterization of the kringle fold and identification of a ubiquitous new class of disulfide rotamers.
The disulfide-bridged chains in the kringle (K) and fibronectin type II (FN2) domains are characterized using a taxonomy that considers the regularities in both beta-secondary structure and cystine cluster. The structural core of the kringle fold comprises an assembly of two beta-hairpins (a "beta-meander") accommodating two overlapping disulfides; one cystine is incorporated in adjacent beta-strands, whereas the other is located just beyond the ends of non-adjacent beta-strands. The dispositions of the (N, C) termini of the two overlapping disulfides in the kringle fold are given as (m, j+1) and (i-1, k+1), in which m, i, j, and k (m<i<j<k) are residues fulfilling the relations m ~(w)j+3 and i ~(n)j~(w)k, where the relationship ~(n/w) associates residues belonging to a narrow/wide hydrogen-bonded pair of an antiparallel beta-sheet. This pattern is the structural signature of the kringle fold and is referred to as the "disulfide kringle-cross". The metrics of this motif are quantified, revealing structural differences between the two families of the kringle fold. The conformations of disulfides in the kringle fold are poorly accommodated by existing classification schemes. To elucidate the nature of these rotamers we have performed density functional theory (DFT) calculations for diethyl disulfide. A new classification for the disulfide conformations in proteins is proposed, consisting of six rotamer types: spiral, trans-spiral, corner, trans, hook, and staple. Its relation with previous classification schemes is specified. A survey of high-resolution X-ray structures reveals that the disulfide conformations are clustered around the averaged conformations for the six classes. Average conformation dihedral and distance values are in excellent agreement with the DFT values. The two overlapping disulfides in kringle domains adopt the trans-spiral conformation that appears to be ubiquitous (~17%) in proteins. One of the disulfides stretches across the beta-meander, invoking "strain" in the disulfide conformational state. The relevance of the new classification and the concept of strain are briefly discussed in the context of disulfide bond cleavage in proteins.
Ozhogina
Olga A
OA
Department of Chemistry, Carnegie Mellon University, Pittsburgh, PA 15213, USA. oao.sputnik@gmail.com
Bominaar
Emile L
EL
D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D004220:Disulfides / Q000737:chemistry*; D006801:Humans; D018082:Kringles; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid
D004220:Disulfides