Common features in structures and sequences of sandwich-like proteins.

The goal of this work is to define the structural and sequence features common to sandwich-like proteins (SPs), a group of very different proteins now comprising 69 superfamilies in 38 protein folds. Analysis of the arrangements of strands within main sandwich sheets revealed a rigorously defined constraint on the supersecondary substructure that holds true for 94% of known SP structures. The invariant substructure consists of two interlocked pairs of neighboring beta-strands. It is even more typical for centers of SP than the well-known "Greek key" strands arrangement for their edges. As homology among these proteins is not usually detectable even with the most powerful sequence-comparing algorithms, we employed a structure-based approach to sequence alignment. Within the interlocked strands we found 12 positions with fixed structural roles in SP. A residue at any of these positions possesses similar structural properties with residues in the same position of other SPs. The 12 positions lie at the center of the interface between the beta-sheets and form the common geometrical core of SPs. Of the 12 positions, 8 are occupied by only four hydrophobic residues in 80% of all SPs.