Origin of bacterial transmembrane -barrels by multiple duplication of a hairpin

Abstract: How did today’s complex protein domains originate? We believe that protein domains arose as combinations of peptide modules that originally evolved as cofactors in the RNA world [SL03]. Here, we investigate the hypothesis that the hairpin that forms the repeating structural unit of the transmembrane -barrels (TMBBs) represents such an ancestral peptide. Despite the obvious structural similarity between TMBBs and the resulting amphipathic character of their sequences, sequence similarity is hardly detectable [NLL95] and evidence for a common ancestry of all bacterial TMBBs has not been found. We use three approaches to test the hypothesis that TMBBs originated by multiple duplication of an ancestral hairpin. First, we investigate the evolutionary relationship between the various groups of TMBB proteins. Second, we look for the hairpin repeats in the sequences of TMBBs with a novel, highly sensitive de-novo repeat detection method. Finally, we combine analysis of structural and sequence similarity to show that the observed sequence similarity between TMBBs cannot be explained by structural constraints on the sequence and hence is a sign of their common origin. In the rst approach, we use a sensitive remote homology detection method (HHsenser) that performs exhaustive transitive prole search using HMM-HMM comparison [SRBL06]. Starting from single TMBBs we are able to nd most known groups of bacterial TMBBs. To get maximum coverage, we pool the largely overlapping results from 17 HHsenser searches started from representative TMBBs with known structure. A clustermap of these proteins was generated by CLANS [FL04] (Fig 1) and all clusters in the map were analyzed and annotated. Strikingly, all known groups of bacterial TMBBs can be found except the non-canonical TMBBs