BETAWRAP: successful prediction of parallel beta -helices from primary sequence reveals an association with many microbial pathogens

Abstract

The amino acid sequence rules that specify beta-sheet structure in proteins remain obscure. A subclass of beta-sheet proteins, parallel beta-helices, represent a processive folding of the chain into an elongated topologically simpler fold than globular beta-sheets. In this paper, we present a computational approach that predicts the right-handed parallel beta-helix supersecondary structural motif in primary amino acid sequences by using beta-strand interactions learned from non-beta-helix structures. A program called BETAWRAP (http://theory.lcs.mit.edu/betawrap) implements this method and recognizes each of the seven known parallel beta-helix families, when trained on the known parallel beta-helices from outside that family. BETAWRAP identifies 2,448 sequences among 595,890 screened from the National Center for Biotechnology Information (NCBI; http://www.ncbi.nlm.nih.gov/) nonredundant protein database as likely parallel beta-helices. It identifies surprisingly many bacterial and fungal protein sequences that play a role in human infectious disease; these include toxins, virulence factors, adhesins, and surface proteins of Chlamydia, Helicobacteria, Bordetella, Leishmania, Borrelia, Rickettsia, Neisseria, and Bacillus anthracis. Also unexpected was the rarity of the parallel beta-helix fold and its predicted sequences among higher eukaryotes. The computational method introduced here can be called a three-dimensional dynamic profile method because it generates interstrand pairwise correlations from a processive sequence wrap. Such methods may be applicable to recognizing other beta structures for which strand topology and profiles of residue accessibility are well conserved.

Figure 1

(A) Side view of x-ray crystal structure (1) of Pectate lyase C from Erwinia chrysanthemi, residue 102–258, generated using the molecular graphics program rasmol (29). (B) Top view of a single rung of a β-helix (residues 242–263 of A), with β-strands B1 in yellow, B2 in green, and B3 in blue, and the intervening turns T1, T2 (in red), and T3. The alternating pattern of the strands before and after T2 and the T2 turn itself are conserved across the superfamily (3, 8).

Figure 2

Histogram of the protein Z-scores as computed by betawrap. The β-helix scores (12 proteins) were superimposed on the scores of the PDB-minus database (1,346 proteins), with the 1,091 proteins that could not be successfully wrapped given the arbitrary score −3.5. The β-helix histogram is in blue, and PDB-minus is in green. The following lists the three top-scoring non-β-helix proteins (PDB name, betawrap score, SCOP superfamily): 4SBV:A, 1.87, eight-stranded β-sandwich; 3TDT, 1.84, left-handed parallel β-helix; 1B35C, 1.83, eight-stranded β-sandwich.