Evolutionary origin of a secondary structure: π-helices as cryptic but widespread insertional variations of α-helices that enhance protein functionality.
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.
Cooley
Richard B
RB
Department of Biochemistry and Biophysics, 2011 Ag and Life Sciences Building, Oregon State University, Corvallis, OR 97331, USA.
Arp
Daniel J
DJ
Karplus
P Andrew
PA
D000595:Amino Acid Sequence; D019143:Evolution, Molecular; D005293:Ferritins / Q000737:chemistry / Q000235:genetics; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D010802:Phylogeny; D017433:Protein Structure, Secondary / Q000235:genetics*; D011506:Proteins / Q000737:chemistry* / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics
D011506:Proteins; D005293:Ferritins