Patterns of structure and sequence in the Kunitz inhibitors interleukins-1-beta adn 1-alpha and fibroblast growth factors

• Published in: Journal of molecular biology Vol. 223; no. 2; pp. 531 - 543
• Main Authors: Murzin, A.G, Lesk, A.M, Chothia, C
• Format: Journal Article
• Language: English
• Published: 1992
• Subjects: amino acid sequences; beta-sheet barrels; comparisons; Erythrina caffra; growth factors; interleukin-1; molecular conformation; molecular sequence data; polyhedron models; proteinase inhibitors; ricin; sequence alignments; sequence determinants of folds
• ISSN: 0022-2836; 1089-8638

Previous crystallographic analyses of the Kunitz inhibitors from soybean, Erythrina caffra and wheat, the interleukins-1 beta and 1 alpha and the acidic and basic fibroblast growth factors have shown that they contain a most unusual fold. It is formed by six two-stranded hairpins. Three of these form a barrel structure and the other three, are in a triangular array that caps the barrel. The arrangement of the secondary structures gives the molecules a pseudo 3-fold axis. Although the different proteins have very similar structures, many of their sequences have no significant similarities overall. The structural determinants of this fold are described and discussed in this paper. The barrels in the different proteins have the same geometrical features: six strands tilted at 56 degrees to the barrel axis; a barrel diameter of 16 angstrom, and the beta-sheet hydrogen bonded so that it is staggered with a shear number of 12. These features fit McLachlan's equations for ideal barrels formed by beta-sheets. The wide diameter of the barrels is filled by layers of residues that, while not identical in the different proteins, are, in almost all cases, large. The structure of the triangular array of hairpins is determined by the coiling of the strands and the packing of hairpin residues against each other and against residues from the interior of the barrel. The major sequence requirements of this fold are large or medium hydrophobic residues at 18 buried sites. In the different structures the total volume of these residues is 3000(+/-120) angstrom 3. The polyhedron model of protein architecture is used to demonstrate that the main, and in particular the symmetrical, features of this fold arise from the ideal and equal packing of six hairpins, modified only slightly to form hydrogen bonds between the hairpins.