4.6 Article

β-Propeller Blades as Ancestral Peptides in Protein Evolution

Journal

PLOS ONE
Volume 8, Issue 10, Pages -

Publisher

PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0077074

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Funding

  1. Max-Planck-Society

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Proteins of the beta-propeller fold are ubiquitous in nature and widely used as structural scaffolds for ligand binding and enzymatic activity. This fold comprises between four and twelve four-stranded beta-meanders, the so called blades that are arranged circularly around a central funnel-shaped pore. Despite the large size range of beta-propellers, their blades frequently show sequence similarity indicative of a common ancestry and it has been proposed that the majority of beta-propellers arose divergently by amplification and diversification of an ancestral blade. Given the structural versatility of beta-propellers and the hypothesis that the first folded proteins evolved from a simpler set of peptides, we investigated whether this blade may have given rise to other folds as well. Using sequence comparisons, we identified proteins of four other folds as potential homologs of beta-propellers: the luminal domain of inositol-requiring enzyme 1 (IRE1-LD), type II beta-prisms, beta-pinwheels, and WW domains. Because, with increasing evolutionary distance and decreasing sequence length, the statistical significance of sequence comparisons becomes progressively harder to distinguish from the background of convergent similarities, we complemented our analyses with a new method that evaluates possible homology based on the correlation between sequence and structure similarity. Our results indicate a homologous relationship of IRE1-LD and type II beta-prisms with beta-propellers, and an analogous one for beta-pinwheels and WW domains. Whereas IRE1-LD most likely originated by fold-changing mutations from a fully formed PQQ motif beta-propeller, type II beta-prisms originated by amplification and differentiation of a single blade, possibly also of the PQQ type. We conclude that both beta-propellers and type II beta-prisms arose by independent amplification of a blade-sized fragment, which represents a remnant of an ancient peptide world.

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