Abstract
The association of two or more proteins to adopt a quaternary complex is one of the most widespread mechanisms by which protein function is modulated. In this scenario, three-dimensional domain swapping (3D-DS) constitutes one plausible pathway for the evolution of protein oligomerization that exploits readily available intramolecular contacts to be established in an intermolecular fashion. However, analysis of the oligomerization kinetics and thermodynamics of most extant 3D-DS proteins shows its dependence on protein unfolding, obscuring the elucidation of the emergence of 3D-DS during evolution, its occurrence under physiological conditions, and its biological relevance. Here, we describe the human FoxP subfamily of transcription factors as a feasible model to study the evolution of 3D-DS, due to their significantly faster dissociation and dimerization kinetics and lower dissociation constants in comparison to most 3D-DS models. Through the biophysical and functional characterization of FoxP proteins, relevant structural aspects highlighting the evolutionary adaptations of these proteins to enable efficient 3D-DS have been ascertained. Most biophysical studies on FoxP suggest that the dynamics of the polypeptide chain are crucial to decrease the energy barrier of 3D-DS, enabling its fast oligomerization under physiological conditions. Moreover, comparison of biophysical parameters between human FoxP proteins in the context of their minute sequence differences suggests differential evolutionary strategies to favor homoassociation and presages the possibility of heteroassociations, with direct impacts in their gene regulation function.
Highlights
Oligomerization into quaternary structures is one of the most determinant aspects by which proteins modulate or even gain new functions [1,2]
No extant monomeric histones exist in nature, direct experimental evidence of the role of 3D-DS in the emergence of the dimeric histone fold was provided by adding a three-residue “insertion” (Gly-Thr-Pro), which is located in the middle of what otherwise would be the long helix in the histone fold of the C-domain of Escherichia coli RuvB, within the hinge region of the archaeal HMfB histone
Equilibrium unfolding experiments and molecular dynamics showed that this protonation decreases the global and local stability of FoxP1 by interrupting specific sidechain–backbone interactions between the imidazole group and a near-peptide bond located in the same helix
Summary
Oligomerization into quaternary structures is one of the most determinant aspects by which proteins modulate or even gain new functions [1,2]. No extant monomeric histones exist in nature, direct experimental evidence of the role of 3D-DS in the emergence of the dimeric histone fold was provided by adding a three-residue “insertion” (Gly-Thr-Pro), which is located in the middle of what otherwise would be the long helix in the histone fold of the C-domain of Escherichia coli RuvB, within the hinge region of the archaeal HMfB histone. This insertion disrupted the dimerization of HMfB and generated a soluble and stable monomer with properties consistent with a four-helix-bundle protein [14]. These results supported the idea that the dimeric histone fold originated through domain-swapping of two four-helix bundle monomers [14], providing compelling evidence of 3D-DS as a plausible evolutionary pathway for the origin of oligomeric structures in nature
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