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A mutation at the dimer interface of Plasmodium falciparum triosephosphate isomerase (PfTIM) was created by mutating a tyrosine residue at position 74, at the subunit interface, to glycine. Tyr74 is a critical residue, forming a part of an aromatic cluster at the interface. The resultant mutant, Y74G, was found to have considerably reduced stability compared with the wild-type protein (TIMWT). The mutant was found to be much less stable to denaturing agents such as urea and guanidinium chloride. Fluorescence and circular dichroism studies revealed that the Y74G mutant and TIMWT have similar spectroscopic properties, suggestive of similar folded structures. Further, the Y74G mutant also exhibited a concentration-dependent loss of enzymatic activity over the range 0.1-10 microM. In contrast, the wild-type enzyme did not show a concentration dependence of activity in this range. Fluorescence quenching of intrinsic tryptophan emission was much more efficient in case of Y74G than TIMWT, suggestive of greater exposure of Trp11, which lies adjacent to the dimer interface. Analytical gel filtration studies revealed that in Y74G, monomeric and dimeric species are in dynamic equilibrium, with the former predominating at low protein concentration. Spectroscopic studies established that the monomeric form of the mutant is largely folded. Low concentrations of urea also drive the equilibrium towards the monomeric form. These studies suggest that the replacement of tyrosine with a small residue at the interface of triosephosphate isomerase weakens the subunit-subunit interactions, giving rise to structured, but enzymatically inactive, monomers at low protein concentration.

Subunit interface mutation disrupting an aromatic cluster in Plasmodium falciparum triosephosphate isomerase: effect on dimer stability