4.5 Review

The Non-native Disulfide-Bond-Containing Landscape Orthogonal to the Oxidative Protein-Folding Trajectory: A Necessary Evil?

Journal

JOURNAL OF PHYSICAL CHEMISTRY B
Volume 126, Issue 49, Pages 10273-10284

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acs.jpcb.2c04648

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This review article discusses the role of non-native disulfide bond-containing species in oxidative protein folding, and explores their existence by projecting the regeneration pathway onto a Cartesian coordinate system and superimposing the folding funnel onto the regeneration trajectory.
Oxidative protein folding describes the process by which disulfide-bond containing proteins mature from their ribosomal, fully reduced and unfolded, origins. Over the past 40 years, a number of exemplar proteins including bovine pancreatic ribonuclease A (RNaseA), bovine pancreatic trypsin inhibitor (BPTI), and hen egg-white lysozyme (HEWL), among others, have provided rich insight into the nature of the intermolecular interactions that drive the formation of the native, biologically active fold. In this Review Article, we revisit the oxidative folding process of RNase A with a focus on reconciling the role of non-native disulfide bond-containing species that populate the oxidative folding landscape. Toward gaining such an understanding, we project the regeneration pathway onto a Cartesian coordinate system. This helps not only to recognize the magnitude of the seemingly fruitless, non-native disulfide bond-containing species that lie orthogonal to the native-protein-forming reaction progress but also to reconcile a role for their existence in the regenerative trajectory. Finally, we superimpose the folding funnel onto the regeneration trajectory to draw parallels between oxidative folders and conformational folders (proteins that lack disulfide bonds). The overall objective is to provide the reader with a semi-quantitative description of oxidative protein folding and the barriers to successful regeneration while underscoring a role of seemingly fruitless intermediates.

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