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DOE OSTI · 2536720

Sequence-defined structural transitions by calcium-responsive proteins

Chang, Marina P.·Huang, Winnie·Shambharkar, Gatha M.·Hernandez, Kenny M.·Mai, Danielle J.
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Abstract

Biopolymer sequences dictate their functions, and protein-based polymers are a promising platform to establish sequence–function relationships for novel biopolymers. To efficiently explore vast sequence spaces of natural proteins, sequence repetition is a common strategy to tune and amplify specific functions. This strategy is applied to repeats-in-toxin (RTX) proteins with calcium-responsive folding behavior, which stems from tandem repeats of the nonapeptide GGXGXDXUX in which X can be any amino acid and U is a hydrophobic amino acid. To determine the functional range of this nonapeptide, we modified a naturally occurring RTX protein that forms β-roll structures in the presence of calcium. Sequence modifications focused on calcium-binding turns within the repetitive region, including either global substitution of nonconserved residues or complete replacement with tandem repeats of a consensus nonapeptide GGAGXDTLY. Some sequence modifications disrupted the typical transition from intrinsically disordered random coils to folded β rolls, despite conservation of the underlying nonapeptide sequence. Proteins enriched with smaller, hydrophobic amino acids adopted secondary structures in the absence of calcium and underwent structural rearrangements in calcium-rich environments. In contrast, proteins with bulkier, hydrophilic amino acids maintained intrinsic disorder in the absence of calcium. In conclusion, these results indicate a significant role of nonconserved amino acids in calcium-responsive folding, thereby revealing a strategy to leverage sequences in the design of tunable, calcium-responsive biopolymers.

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY59 BASIC BIOLOGICAL SCIENCES

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Chang, Marina P., Huang, Winnie, Shambharkar, Gatha M., Hernandez, Kenny M., Mai, Danielle J.. 2024-11-08. Sequence-defined structural transitions by calcium-responsive proteins. https://doi.org/10.1039/d4py00907j

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