A protein's conformational stability is an immunologically dominant factor: Evidence that free-energy barriers for protein unfolding limit the immunogenicity of foreign proteins

Takatoshi Ohkuri, Satoko Nagatomo, Kenji Oda, Takanori So, Taiji Imoto, Tadashi Ueda

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)

Abstract

Foreign protein Ags are incorporated into APCs and then degraded by endosomal proteases. The peptides are then mounted on MHC II molecules on the surfaces of APCs. The T cell-triggering response and, therefore, the immune response, were suggested to be governed by the degree of conformational stability of the foreign protein Ags. However, there is little evidence that a protein's conformational stability is an immunologically dominant factor. In this study, we show that a protein has a threshold of conformational stability to prevent the immunogenicity of foreign proteins. Inverse and linear correlations were found between the amount of IgG production against lysozymes and the free-energy change for the unfolding of lysozymes, based on the correlation between the free-energy changes of the protein unfolding and the amount of IgG production against lysozymes with different stabilities in mice using hen egg white lysozyme derivatives and mutant mouse lysozymes, in which the sequence between 107 and 116 is replaced with that of hen egg white lysozyme, which can produce autoantibodies in mice. Interestingly, the thresholds of free-energy changes for both lysozymes to prevent their immunogenicity were almost identical (21-23 kcal/mol). To confirm the results, we also showed that the cross-linking of Phl p 7, in which intact Phl p 7 has stability greater than ∼20 kcal/mol under physiological conditions, induced minimal IgG production in mice, whereas intact Phl p 7 was antigenic. From the above results, we suggest that protein conformational stability was an immunologically dominant factor.

Original languageEnglish
Pages (from-to)4199-4205
Number of pages7
JournalJournal of Immunology
Volume185
Issue number7
DOIs
Publication statusPublished - 2010 Oct 1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint

Dive into the research topics of 'A protein's conformational stability is an immunologically dominant factor: Evidence that free-energy barriers for protein unfolding limit the immunogenicity of foreign proteins'. Together they form a unique fingerprint.

Cite this