New protein folds can evolve from preexisting folds, but the consequences of evolving a new fold are still largely unclear. In the Cro family, an α+β fold has evolved from an all-α fold and displays a rearranged dimer interface essential to its function in DNA binding. There are two major groups of Cro proteins with the α+β fold, one of which (lambda group) is derived from the other (Pfl6 group). The older group shows weaker dimerization as well as conformational strain in a turn between two helices, probably resulting from the α-to-β fold switch. Sequential and structural comparison suggests that the strain was relieved in the derived group through a deletion mutation, while dimerization was strengthened by formation of a deep “ball and socket” interface. A third, smaller group of α+β Cro proteins (exemplified by EGH42792) is also derived from the Pfl6 group and appears to have acquired a deletion mutation at a position adjacent to the deletion found in lambda. To determine whether this mutation represents a second, independent evolutionary path to fix the conformational strain, we studied the structure of EGH42792 using NMR spectroscopy. A preliminary CS-ROSETTA structure suggests that the deletion may lead to strain relief by a different structural mechanism from that observed in lambda. EGH42792 also lacks the ball-and-socket dimer interface of lambda, but a sedimentation equilibrium experiment gave a <i>K</i><sub>d</sub> for dimerization of ~58 ± 22 μM, intermediate between the dimerization strength of lambda and Pfl 6, suggesting that EGH42792 may also represent a second evolutionary path to stronger dimerization. Our results suggest that evolutionary pressures may lead to convergent evolution of similar changes in structural properties of protein folds through parallel mutational paths.

Seeing double: Evolution may utilize multiple parallel paths to optimize new protein folds

249th National Meeting (2015)

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