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Deletion mutants of human interleukin 1β with significantly reduced agonist properties: Search for the agonist/antagonist switch in ligands to the interleukin 1 receptors

Academic Article
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Overview

authors

  • Simoncsits, A.
  • Bristulf, J.
  • Tjornhammar, M. L.
  • Cserzo, M.
  • Pongor, S.
  • Rybakina, E.
  • Gatti, S.
  • Bartfai, Tamas

publication date

  • March 1994

journal

  • Cytokine  Journal

abstract

  • The existence of an endogenous high affinity interleukin 1 receptor antagonist (IL-1ra) suggests that this molecule lacks some structural motif(s) which are present in the closely homologous agonist interleukin 1 beta (IL-1 beta) and which serve as the 'agonist switch' causing signal transduction by the agonist-receptor complex. The primary sequence alignment of IL-1 beta and IL-1ra sequences from different species reveals a six amino acid long motif that is quasi conserved among IL-1 beta sequences, but is missing from the IL-1ra sequences. The three-dimensional structure of human IL-1 beta was used as a template for building structural models of deletion mutants (delta SND 52-54 and delta EESNDK 50-55) using molecular graphics. These models indicated that the middle three residues SND 52-54 from the EESNDK 50-55 loop may be deleted without causing major changes in the tertiary structure of the mutant as compared to that of IL-1 beta. Residues SND 52-54 from the above loop were deleted. When compared with IL-1 beta the IL-1 beta-delta SND analog (delta SND 52-54) binds with the same affinity to type 2 IL-1 receptor but with a more than 10-fold lower affinity to type 1 IL-1 receptor. Despite of this small decrease in affinity at the type 1 receptor the delta SND 52-54 has a 1000-fold lower biological activity than IL-1 beta when tested in a thymocyte activating factor assay.(ABSTRACT TRUNCATED AT 250 WORDS)

subject areas

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Binding, Competitive
  • Cattle
  • DNA Primers
  • Humans
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1
  • Ligands
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis
  • Protein Structure, Secondary
  • Rabbits
  • Rats
  • Receptors, Interleukin-1
  • Recombinant Proteins
  • Sequence Deletion
  • Sequence Homology, Amino Acid
  • Sheep
  • Sialoglycoproteins
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Research

keywords

  • BINDING EPITOPE
  • DELETION MUTANT
  • INTERLEUKIN 1 RECEPTOR ANTAGONIST
  • INTERLEUKIN 1 RECEPTORS
  • MODELING
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Identity

International Standard Serial Number (ISSN)

  • 1043-4666

Digital Object Identifier (DOI)

  • 10.1016/1043-4666(94)90043-4

PubMed ID

  • 8032002
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Additional Document Info

start page

  • 206

end page

  • 214

volume

  • 6

issue

  • 2

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