Aromatic-histidine interactions in the zinc finger motif: structural inequivalence of phenylalanine and tyrosine in the hydrophobic core.
The classical Zn finger (Cys-X2,4-Cys-X3-Phe-X5-Leu-X2-His-X3,4-His contains [corrected] an aromatic-histidine interaction (underlined) in its hydrophobic core whose importance is suggested by the marked destabilization of a Phe-->Leu analogue [Mortishire-Smith, R.J., Lee, M.S., Bolinger, L., & Wright, P.E. (1992) FEBS Lett. 1, 11-15]. In some Zn finger sequences the central Phe is replaced [corrected] by Tyr, and when present, this substitution is generally conserved among species. To investigate whether Tyr would participate in an analogous aromatic-histidine interaction, we have determined the solution structure in a Phe-->Tyr mutant domain. Its global fold (the beta beta alpha motif) is similar to that of the Phe domain. Although the variant Tyr maintains edge-to-face packing against the proximal histidine, the phenolic ring is displaced toward solvent. Such displacement increases the solvent accessibility of the Tyr p-OH group and reduces steric overlap (and possible electrostatic repulsion) between the Tyr O zeta and His pi electrons. The Tyr analogue exhibits reduced dynamic stability (as indicated by more rapid exchange of amide protons in D2O) and may alternate in rapid equilibrium between major and minor conformers. Inequivalent Tyr-His and Phe-His interactions are likely to be general features of Zn finger architecture. Molecular modeling based on the Zif268 cocrystal structure [Pavletich, N.P., & Pabo, C.O. (1991) Science 252, 809-817] suggests that the variant Tyr p-OH group may readily be positioned to contribute a novel hydrogen bond to a DNA phosphate.
Jasanoff
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Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.
Weiss
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MA
D000595:Amino Acid Sequence; D002942:Circular Dichroism; D006639:Histidine; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D010649:Phenylalanine; D011487:Protein Conformation; D014443:Tyrosine; D016335:Zinc Fingers
D010455:Peptides; D014443:Tyrosine; D010649:Phenylalanine; D006639:Histidine