Multiple amino acid substitutions suggest a structural basis for the separation of biological activity and receptor binding in a mutant interleukin-1 beta protein
| Autor: | Philip E. Auron, Lanny J. Rosenwasser, Lee Gehrke, Gary J. Quigley |
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| Rok vydání: | 1992 |
| Předmět: |
Models
Molecular Arginine Stereochemistry Macromolecular Substances Protein Conformation Molecular Sequence Data Biology Lymphocyte Activation Biochemistry Cell Line Protein structure X-Ray Diffraction Mutant protein Humans Amino Acid Sequence Receptors Immunologic Peptide sequence chemistry.chemical_classification Alanine Dose-Response Relationship Drug Receptors Interleukin-1 Biological activity Glutamic acid T-Lymphocytes Helper-Inducer Recombinant Proteins Amino acid chemistry Mutagenesis Site-Directed Interleukin-1 |
| Zdroj: | Biochemistry. 31(29) |
| ISSN: | 0006-2960 |
| Popis: | Receptor binding and biological activity properties of human interleukin-1 beta can be dissociated by mutating a single amino acid, arginine 127, to glycine (IL-1 beta R----G) [Gehrke et al. (1990) J. Biol. Chem. 265, 5922-5925]. The mechanism underlying the reduced biological activity has been examined by replacing arginine 127 with several other amino acids, followed by determination of biological activity using a T-helper cell proliferation assay. Mutant IL-1 beta proteins containing lysine, glutamic acid, tryptophan, or alanine in place of arginine 127 maintain biological activity. These data strongly suggest that IL-1 beta biological activity is not directly dependent upon the specific properties of charge, hydrophobicity/hydrophilicity, or side-chain group presented by the residue at position 127. Molecular modeling analyses indicate that the structural integrity of the antiparallel beta-strand 1/12 pair is disturbed in the glycine 127 mutant protein. Collapse of beta-strand 1 into a hydrated space between strands 1, 2, and 4 could structurally alter a cleft in IL-1 beta that contains a cluster of highly conserved amino acids, including a key aspartic acid residue [Ju et al. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 2658-2662]. Mutagenesis data and the differential activities of the IL-1 beta R----G and IL-1 receptor antagonist proteins in stimulating early and late gene expression [Conca et al. (1991) J. Biol. Chem. 266, 16265-16268] suggest that multiple receptor-ligand contacts, exclusive of those required for receptor binding, are required for the stimulation of full IL-1 biological activity. |
| Databáze: | OpenAIRE |
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