Conservation of the Folding Mechanism between Designed Primordial (βα)8-Barrel Proteins and Their Modern Descendant
2012
Carstensen, Linn | Sperl, Josef M. | Bocola, Marco | List, Felix | Schmid, Franz X. | Sterner, Reinhard
The (βα)₈-barrel is among the most ancient, frequent, and versatile enzyme structures. It was proposed that modern (βα)₈-barrel proteins have evolved from an ancestral (βα)₄-half-barrel by gene duplication and fusion. We explored whether the mechanism of protein folding has remained conserved during this long-lasting evolutionary process. For this purpose, potential primordial (βα)₈-barrel proteins were constructed by the duplication of a (βα)₄ element of a modern (βα)₈-barrel protein, imidazole glycerol phosphate synthase (HisF), followed by the optimization of the initial construct. The symmetric variant Sym1 was less stable than HisF and its crystal structure showed disorder in the contact regions between the half-barrels. The next generation variant Sym2 was more stable than HisF, and the contact regions were well resolved. Remarkably, both artificial (βα)₈-barrels show the same refolding mechanism as HisF and other modern (βα)₈-barrel proteins. Early in folding, they all equilibrate rapidly with an off-pathway species. On the productive folding path, they form closely related intermediates and reach the folded state with almost identical rates. The high energy barrier that synchronizes folding is thus conserved. The strong differences in stability between these proteins develop only after this barrier and lead to major changes in the unfolding rates. We conclude that the refolding mechanism of (βα)₈-barrel proteins is robust. It evolved early and, apparently, has remained conserved upon the diversification of sequences and functions that have taken place within this large protein family.
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