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Structural modifications of interleukin-2 at positions 47 and 65

B L Lee1, T L Ciardelli

  • 1Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA. Betty.Lee@UCHSC.edu

Biochemical and Biophysical Research Communications
|April 17, 1997
PubMed
Summary

Altering the proline residue in Interleukin-2 (IL-2) affects its bioactivity and receptor binding. Specific mutations, like Asn-47 and Asp-47, significantly reduce IL-2 function, creating partial agonists.

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Area of Science:

  • * Protein Biochemistry
  • * Molecular Biology
  • * Immunology

Background:

  • * Interleukin-2 (IL-2) is a critical cytokine for T-cell growth and proliferation.
  • * Proline residues can introduce kinks in alpha-helices, potentially influencing protein structure and function.
  • * Previous research mistakenly identified Pro-47 as a key helix-disrupting residue.

Purpose of the Study:

  • * To investigate the impact of altering proline residues in IL-2 alpha-helices on protein bioactivity and conformation.
  • * To understand the role of Pro-47 and Pro-65 in IL-2 structure-function relationships.

Main Methods:

  • * Site-directed mutagenesis was used to create mutants at Pro-47 and Pro-65 positions.
  • * Various amino acid substitutions (acidic, neutral, helix-stabilizing) were introduced.

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  • * Bioactivity and binding affinity (Kd) to high-affinity receptors were measured for the mutants.

    • Main Results:

    • * Mutants Asn-47 and Asp-47 showed significantly reduced bioactivity (50- and 700-fold decreases) and increased Kd to high-affinity receptors (180- and 90-fold increases).
    • * These mutations resulted in partial agonists, indicating altered protein conformation and disrupted hydrophobic packing.
    • * Gly-47, Gly-65, and Ala-65 mutations had less pronounced effects on bioactivity and binding affinities.

    Conclusions:

    • * Specific proline substitutions, particularly at position 47, critically impact IL-2 bioactivity and receptor binding by altering protein conformation.
    • * Asn-47 and Asp-47 substitutions disrupt the protein's hydrophobic core, leading to partial agonism.
    • * Pro-65 appears less critical for IL-2 function, suggesting conservative mutations are tolerated at this site.