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Role of the C-terminal chain in human interferonγ stability: An electrostatic study

2001; Wiley; Volume: 43; Issue: 2 Linguagem: Inglês

10.1002/1097-0134(20010501)43

1097-0134

Gioia Altobelli, Genoveva Nacheva, Kristina Todorova, Ivan Ivanov, Andrey Karshikoff,

Synthesis and biological activity

Proteins: Structure, Function, and BioinformaticsVolume 43, Issue 2 p. 125-133 Research Article Role of the C-terminal chain in human interferonγ stability: An electrostatic study Gioia Altobelli, Gioia Altobelli Department of Biosciences at Novum, Karolinska Institutet, Huddinge, SwedenSearch for more papers by this authorGenoveva Nacheva, Genoveva Nacheva Institute of Molecular Biology, Bulgarian Academy of Sciences, Sofia, BulgariaSearch for more papers by this authorKristina Todorova, Kristina Todorova Institute of Molecular Biology, Bulgarian Academy of Sciences, Sofia, BulgariaSearch for more papers by this authorIvan Ivanov, Ivan Ivanov Institute of Molecular Biology, Bulgarian Academy of Sciences, Sofia, BulgariaSearch for more papers by this authorAndrey Karshikoff, Corresponding Author Andrey Karshikoff [email protected] Department of Biosciences at Novum, Karolinska Institutet, Huddinge, SwedenDepartment of Biosciences at Novum, Karolinska Institutet, S-14157 Huddinge, Sweden===Search for more papers by this author Gioia Altobelli, Gioia Altobelli Department of Biosciences at Novum, Karolinska Institutet, Huddinge, SwedenSearch for more papers by this authorGenoveva Nacheva, Genoveva Nacheva Institute of Molecular Biology, Bulgarian Academy of Sciences, Sofia, BulgariaSearch for more papers by this authorKristina Todorova, Kristina Todorova Institute of Molecular Biology, Bulgarian Academy of Sciences, Sofia, BulgariaSearch for more papers by this authorIvan Ivanov, Ivan Ivanov Institute of Molecular Biology, Bulgarian Academy of Sciences, Sofia, BulgariaSearch for more papers by this authorAndrey Karshikoff, Corresponding Author Andrey Karshikoff [email protected] Department of Biosciences at Novum, Karolinska Institutet, Huddinge, SwedenDepartment of Biosciences at Novum, Karolinska Institutet, S-14157 Huddinge, Sweden===Search for more papers by this author First published: 15 February 2001 https://doi.org/10.1002/1097-0134(20010501)43:2 3.0.CO;2-JCitations: 8Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Abstract Electrostatic interactions in two structures of human interferon gamma (hIFNγ), corresponding to interferon molecule alone and bound to its receptor, were analyzed on the basis of a continuum dielectric model. It was found that a number of titratable groups, mainly basic, show large pK shifts and remain in their neutral forms at physiologically relevant pH. The fact that these groups are largely common to both structures and that most of them belong to the set of most conserved sites suggests that this is a property inherent to the hIFNγ molecule rather than an artifact of the crystal packing. His111 was also found deprotonated at neutral pH. It was concluded that receptor recognition involving His111 is driven by aromatic coupling of His111 and Tyr52 from the receptor rather than by electrostatic interactions. The structure corresponding to hIFNγ in complex with its receptor shows a reduction in number and in degree of desolvation of the buried titratable sites. This finding suggested that on receptor binding, hIFNγ adopts energetically more favorable, relaxed, conformation. It was experimentally shown that in contrast to the full-size hIFNγ, the construct having 21 amino acid residues deleted from the C-terminus is soluble. The hydrophobicity profile analysis suggested that factors other than the exposure of hydrophobic parts of the molecule are responsible for the low stability and propensity for aggregation. On the basis of these results, it was assumed that the electrostatic influence of the C-terminal part contributes particularly to the low solvent exposure of the titratable groups, and hence to the low structural stability and propensity for aggregation of the recombinant hIFNγ. Proteins 2001;43:125–133. © 2001 Wiley-Liss, Inc. REFERENCES 1 Ealick SE, Cook WJ, Vijay-Kumar S, et al. 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