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Role of the C‐terminal chain in human interferonγ stability: An electrostatic study
Author(s) -
Altobelli Gioia,
Nacheva Genoveva,
Todorova Kristina,
Ivanov Ivan,
Karshikoff Andrey
Publication year - 2001
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/1097-0134(20010501)43:2<125::aid-prot1024>3.0.co;2-j
Subject(s) - deprotonation , chemistry , titratable acid , static electricity , molecule , receptor , electrostatics , crystal structure , stereochemistry , protein structure , crystallography , biophysics , biochemistry , ion , biology , organic chemistry , electrical engineering , engineering
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.