Did evolution create a flexible ligand-binding cavity ... through deletion of a plesiotypic disulfide bond?

For some reason my employer no longer subscribes to JBC, but I think the abstract speaks for itself. I wonder if we will see our friends at the discovery institute writing about this one?

Often gaining a new function often requires replacing the old function. Behe et al just like re-defining what constitutes a “real” new function and create an artificial hierarchy of adaptive traits in order to argue that biological systems can only go “down” the hierarchy to less complex solutions (never up the hierarchy to more complex adaptions by mutation/natural selection). Of course, how can you compare the complexity of a disulfide bond to the complexity of binding a ligand on their hierarchy?

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The urokinase receptor (uPAR) is a founding member of a small protein family with multiple Ly6/uPAR (LU) domains. The motif defining these LU domains contains five plesiotypic disulfide bonds stabilizing its prototypical three-fingered fold having three protruding loops. Notwithstanding the detailed knowledge on structure-function relationships in uPAR, one puzzling enigma remains unexplored. Why does the first LU domain in uPAR (DI) lack one of its consensus disulfide bonds, when the absence of this particular disulfide bond impairs the correct folding of other single LU domain-containing proteins? Here, using a variety of contemporary biophysical methods, we found that reintroducing the two missing half-cystines in uPAR DI caused the spontaneous formation of the corresponding consensus 7–8 LU domain disulfide bond. Importantly, constraints due to this cross-link impaired (i) the binding of uPAR to its primary ligand urokinase and (ii) the flexible interdomain assembly of the three LU domains in uPAR. We conclude that the evolutionary deletion of this particular disulfide bond in uPAR DI may have enabled the assembly of a high-affinity urokinase-binding cavity involving all three LU domains in uPAR. Of note, an analogous neofunctionalization occurred in snake venom α-neurotoxins upon loss of another pair of the plesiotypic LU domain half-cystines. In summary, elimination of the 7–8 consensus disulfide bond in the first LU domain of uPAR did have significant functional and structural consequences.

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