Deletion mutants of human interleukin 1 beta with significantly reduced agonist properties: search for the agonist/antagonist switch in ligands to the interleukin 1 receptors.
Cytokine
; 6(2): 206-14, 1994 Mar.
Article
in En
| MEDLINE
| ID: mdl-8032002
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)
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Sialoglycoproteins
/
Interleukin-1
/
Receptors, Interleukin-1
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Cytokine
Year:
1994
Document type:
Article