Fluid protein fold space and its implications

• Published in: BioEssays 2023-09, Vol.45 (9), p.e2300057-n/a
• Main Author: Porter, Lauren L.
• Format: Article
• Language: English
• Subjects: Alternative splicing; Amino Acid Sequence; Amino acids; Cellular structure; metamorphic proteins; Models, Molecular; Nucleotides; protein evolution; protein fold switching; Protein Folding; Protein structure; Proteins; Proteins - metabolism; Proteomics; Structure-function relationships; Switching
• ISSN: 0265-9247; 1521-1878; 1521-1878
• DOI: 10.1002/bies.202300057

Fold‐switching proteins, which remodel their secondary and tertiary structures in response to cellular stimuli, suggest a new view of protein fold space. For decades, experimental evidence has indicated that protein fold space is discrete: dissimilar folds are encoded by dissimilar amino acid sequences. Challenging this assumption, fold‐switching proteins interconnect discrete groups of dissimilar protein folds, making protein fold space fluid. Three recent observations support the concept of fluid fold space: (1) some amino acid sequences interconvert between folds with distinct secondary structures, (2) some naturally occurring sequences have switched folds by stepwise mutation, and (3) fold switching is evolutionarily selected and likely confers advantage. These observations indicate that minor amino acid sequence modifications can transform protein structure and function. Consequently, proteomic structural and functional diversity may be expanded by alternative splicing, small nucleotide polymorphisms, post‐translational modifications, and modified translation rates. Fold switching suggests that protein fold space is more fluid than previously realized because homologous amino acid sequences can assume multiple folds with different secondary structure arrangements. In this figure, fold switching allows groups of homologous sequences (colored contours) to span different regions of protein fold space.