Abstract:
:Interleukin-2 (IL-2) is a cytokine essential for the growth and proliferation of T-cells. The purpose of this research was to study the effects of altering the "kink" caused by Pro in an alpha-helix of the protein. The Pro-47 residue was chosen because it was originally, but mistakenly, traced to the kink of an alpha-helix [1]. Pro-65 is now recognized to be situated in the middle of helix B [2]. To study the significance of this Pro for the bioactivity and overall conformation of IL-2 it was mutated to Gly and Ala. We successfully obtained 17 different mutants at position 47 and two mutants at position 65. Certain amino acid substitutions representing different categories of amino acids, namely, acidic, neutral and helix stabilizing, were chosen for more thorough investigation. The results showed that Asn-47 and Asp-47 decreased the bioactivity of these mutants by 50- and 700-fold respectively, while the Kd to its high affinity receptors was increased 180- and 90-fold respectively, compared to IL-2. The intermediate binding affinity of Asn-47 and Asp-47 was decreased 8- and 37-fold, respectively. On the other hand, Gly-47, Gly-65 and Ala-65 showed less dramatic decreases in bioactivity and high affinity binding. The intermediate binding affinity of these mutants decreased from 5- to 3-fold and low affinity binding decreased approximately 4-fold suggesting some structural and conformational changes. From these observations, we conclude that Asn-47 or Asp-47 disrupt the hydrophobic packing of the core and thus changed the overall conformation of the protein, thereby giving rise to partial agonists. Although Pro-65 lies within the helix, it may be near the surface of the protein but may not be the actual binding site and thus any conservative mutation can be better tolerated.
journal_name
Biochem Biophys Res Communjournal_title
Biochemical and biophysical research communicationsauthors
Lee BL,Ciardelli TLdoi
10.1006/bbrc.1997.6453subject
Has Abstractpub_date
1997-04-17 00:00:00pages
309-15issue
2eissn
0006-291Xissn
1090-2104pii
S0006-291X(97)96453-6journal_volume
233pub_type
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