Evolutionary Origin of a Secondary Structure: π-Helices as Cryptic but Widespread Insertional Variations of α-Helices That Enhance Protein Functionality

• Published in: Journal of molecular biology Vol. 404; no. 2; pp. 232 - 246
• Main Authors: Cooley, Richard B., Arp, Daniel J., Karplus, P. Andrew
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 26.11.2010
• Subjects: Amino Acid Sequence; Evolution, Molecular; ferritin-like superfamily; Ferritins - chemistry; Ferritins - genetics; Hydrogen Bonding; Models, Molecular; Molecular Sequence Data; Mutagenesis, Insertional; Phylogeny; protein evolution; Protein Structure, Secondary - genetics; Proteins - chemistry; Proteins - genetics; secondary structure; Sequence Homology, Amino Acid; Thermodynamics; α-aneurism; π-helix; π-helix; secondary structure; BMM; protein evolution; ferritin-like superfamily; RNR; PH; ToMO; α-aneurism; H-bond; MMOH; PDB
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2010.09.034

Formally annotated π-helices are rare in protein structures but have been correlated with functional sites. Here, we analyze protein structures to show that π-helices are the same as structures known as α-bulges, α-aneurisms, π-bulges, and looping outs, and are evolutionarily derived by the insertion of a single residue into an α-helix. This newly discovered evolutionary origin explains both why π-helices are cryptic, being rarely annotated despite occurring in 15% of known proteins, and why they tend to be associated with function. An analysis of π-helices in the diverse ferritin-like superfamily illustrates their tendency to be conserved in protein families and identifies a putative π-helix-containing primordial precursor, a “missing link” intermediary form of the ribonucleotide reductase family, vestigial π-helices, and a novel function for π-helices that we term a “peristaltic-like shift.” This new understanding of π-helices paves the way for this generally overlooked motif to become a noteworthy feature that will aid in tracing the evolution of many protein families, guide investigations of protein and π-helix functionality, and contribute additional tools to the protein engineering toolkit. [Display omitted] ► Most π-helices are evolutionarily derived from α-helices via a one-residue insertion. ► Because they occur in the midst of α-helices, over 95% of π-helices are not annotated. ► π-Helices are useful for guiding insight into a protein's origin and functionality. ► A precursor with a novel diiron center is proposed for the ferritin-like superfamily.