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Molecular Recognition at the Dimer Interface of a Class Mu Glutathione Transferase:  Role of a Hydrophobic Interaction Motif in Dimer Stability and Protein Function†

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Protein Structure-Function Research Programme, School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg 2050, South Africa, and Departments of Biochemistry and Chemistry, Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146
Cite this: Biochemistry 2002, 41, 48, 14238–14247
Publication Date (Web):November 7, 2002
https://doi.org/10.1021/bi020548d
Copyright © 2002 American Chemical Society
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    Abstract

    Cytosolic glutathione (GSH) transferases (GSTs) exist as stable homo- and heterodimers. Interactions at the subunit interface serve an important role in stabilizing the subunit tertiary structures of all GSH transferases. In addition, the dimer is required to maintain functional conformations at the active site on each subunit and the nonsubstrate ligand binding site at the dimer interface [Dirr, H. W. (2001) Chem.-Biol. Interact.133, 19−23]. In this study, we report on the contribution of a specific intersubunit hydrophobic motif in rGSTM1-1 to dimer stability and protein function. The motif consists of the side chain of F56 from one subunit intercalated between helices 4 and 5 of the second subunit. Replacement of F56 with the hydrophilic side chains of serine, arginine, and glutamate results in a change in the structure of the active site, a marked diminution in catalytic efficiency, and alterations in the ability to bind nonsubstrate ligands. The mutations also affect the ability of the enzyme to bind GSH and the substrate analogue glutathione sulfonate. The functionality of rGSTM1-1 was disrupted to the greatest extent for the F56E mutant. Though mutations at this position do not alter the three-state equilibrium folding process for rGSTM1-1 (i.e., N2 ↔ 2I ↔ 2U), destabilizing mutations at position 56 shift the equilibrium between the folded dimer (N2) and the monomeric intermediate (I) toward the latter conformational state. The transition to the unfolded state (U) is not significantly affected. The folded monomeric intermediate is also observed by electrospray ionization mass spectrometry. The amount of the intermediate is dependent on protein concentration and the residue at position 56. Mutations at position 56 have little impact on the secondary structure and stability of the monomeric folding intermediate. The dimerization process is proposed to induce a conformational change in the loop containing F56, resulting in improved stability and increased affinity between the M1 subunits.

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    †

     Supported by the University of the Witwatersrand, the South African Foundation for Research and Development, Wellcome Trust Grant 060799, Forgarty International Collaboration Award TW00779, and Grants R01 GM30910, P30 ES00267, and T32 ES07028 from the National Institutes of Health.

    ‡

     University of the Witwatersrand.

    §

     Vanderbilt University School of Medicine.

    *

     To whom correspondence should be addressed. R.N.A.:  e-mail, [email protected]; fax, (615) 343-2921; telephone, (615) 343-2920. H.W.D.:  e-mail, [email protected]; fax, +27 11 403 1733; telephone, +27 11 717 6352.

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