Abstract
BackgroundSequence similarity between proteins is usually considered a reliable indicator of homology. Pyruvate-ferredoxin oxidoreductase and quinol-fumarate reductase contain ferredoxin domains that bind [Fe-S] clusters and are involved in electron transport. Profile-based methods for sequence comparison, such as PSI-BLAST and HMMer, suggest statistically significant similarity between these domains.ResultsThe sequence similarity between these ferredoxin domains resides in the area of the [Fe-S] cluster-binding sites. Although overall folds of these ferredoxins bear no obvious similarity, the regions of sequence similarity display a remarkable local structural similarity. These short regions with pronounced sequence motifs are incorporated in completely different structural environments. In pyruvate-ferredoxin oxidoreductase (bacterial ferredoxin), the hydrophobic core of the domain is completed by two β-hairpins, whereas in quinol-fumarate reductase (α-helical ferredoxin), the cluster-binding motifs are part of a larger all-α-helical globin-like fold core.ConclusionFunctionally meaningful sequence similarity may sometimes be reflected only in local structural similarity, but not in global fold similarity. If detected and used naively, such similarities may lead to incorrect fold predictions.
Highlights
Sequence similarity between proteins is usually considered a reliable indicator of homology
Structures and functions Here, we suggest that the statistically supported sequence similarity found between two [Fe-S]-containing ferredoxin domains that adopt different structural folds could potentially represent such a case of analogous sequences
Bacterial ferredoxins comprise one of the largest evolutionary lineages of ferredoxins and are present both as individual proteins and as domains incorporated in larger, multi-domain proteins [15,16]
Summary
Sequence similarity between proteins is usually considered a reliable indicator of homology. The millions of species of living organisms on earth possess billions of different proteins. This enormous diversity has evolved from a limited number of ancestral proteins, likely in the range of a few thousand domains [1,2]. It has been argued that due to the size and discreteness of the sequence space, detectable sequence similarity is a reflection of homology [4]. A straightforward way to infer homology is by statistically supported sequence similarity. With a few notable exceptions of proteins possessing biased amino acid composition (low complexity, coiled-coil, transmembrane) that reduces the size of available sequence space, the sequence argument still stands today more than two dec-
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