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Document Page 448 cell-surface receptor and to a recombinant, soluble form of the ligand-binding chain of the receptor [25]. Synthetic peptides corresponding to the sequence of the extracellular domain of the ligand-binding subunit were used to define the region of the receptor to which the N-terminus of IFN-γ binds. Receptor peptide MIR (95–120) competed most strongly with IFN-γ binding to both cell-surface and recombinant, soluble receptor [41]. Additionally, antisera to this peptide and the adjacent overlapping peptide, MIR (118–143), inhibited the binding of IFN-γ to the recombinant, soluble receptor. Therefore, the receptor domain responsible for binding the N-terminus of IFN-γ is defined <strong>by</strong> the region encompassing residues 95–120 of the ligand-binding subunit of the IFN-γ receptor and may extend further into the neighboring sequence. Antibodies to the C-terminal region of IFN-γ have been shown to be potent neutralizers of IFN-γ activity [29]. However, no cell-surface binding site for the C-terminus of IFN-γ could be localized using either antisera or synthetic peptides. Furthermore, as indicated above, the C-terminal IFN-γ peptide, IFN-γ (95–133), competed specifically with the intact IFN-γ molecule for binding to a recombinant, soluble form of the receptor, which consists of both the extracellular and the intracellular domains [42]. It was hypothesized that since the intracellular portion of the soluble receptor was accessible, in contrast to that of the cell-surface receptor, the C-terminus of IFN-γ might indeed be binding to this region. In studies using synthetic peptides corresponding to the cytoplasmic domain of the murine IFN-γ receptor, only peptide MIR (253–287) specifically bound both murine IFN-γ and its C-terminal peptide, MuIFN-γ (95–133) [33]. This peptide corresponds to the membrane proximal region of the receptor's cytoplasmic region. Antibodies to this receptor peptide inhibited the binding of the C-terminus of murine IFN-γ to the receptor in cells which had been fixed and permeabilized. Analogous binding studies with human IFN-γ and its C- terminal peptide, HuIFN-γ (95–134), yielded a similar result [43]. Surprisingly, the binding of the IFN-γ C-terminal peptides to their cytoplasmic binding sites is not species restricted, which is in contrast to the binding of the whole molecule at the cell surface. Both human and murine IFN-γ and their C-terminal peptides bound equally well to receptor peptides of either human or murine origin [43]. Thus, a receptor binding site for the C-terminus of the IFN-γ molecule has been localized to the membrane proximal region of the ligand-binding subunit's cytoplasmic domain (Figure 6). Previously, there have been several reports of human IFN-γ having activity on murine cells when administered cytoplasmically [44–46]. With the identification of a cytoplasmic binding site for IFN-γ, which is not species restricted, the question arose as to whether this might be the basis for these earlier observations. Thus, C-terminal IFN-γ peptides of both human and murine origin were used to stimulate murine macrophage lines P388D 1 WEHI-3. Macrophages were chosen particularly for their capacity to nonspecifically endocytose material, http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_448.html [4/9/2004 12:11:38 AM]
Document Figure 6 Proposed receptor activation pathway for IFN-γ. (From Reference 53. Copyright 1995. The American Association of Immunologists.) Page 449 and we took advantage of this as a means of introducing the IFN-γ peptides into these cells. The IFN-γ Cterminal peptides induced a potent antiviral state in the murine macrophages and upregulated expression of MHC class II molecules, both in a dose-dependent fashion [43]. These effects were demonstrated to be sequence specific, as a scrambled version of the murine C-terminal peptide lacked activity. Furthermore, a truncated form of the murine C-terminal peptide, lacking the sequence of basic amino acids (RKRKR), was also without activity. The absence of activity of this truncated peptide was linked directly to a loss of its ability to bind to the receptor [43]. Therefore, interaction of IFN-γ, via its Cterminus, with its cytoplasmic binding site is important for function and requires the presence of a region of basic amino acids near the C-terminus of the molecule. C. Structural Biology of IFN-γ and the IFN-γ Receptor <strong>Structure</strong>-function studies of IFN-γ carried out using the synthetic peptide approach and site-specific antibodies indicated that both the N- and C-terminal regions of the protein were not only functionally important, but also accessible at the surface of the molecule. The x-ray crystal structure of human IFN-γ has been determined and reveals that in the IFN-γ homodimer both the N- and the http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_449.html [4/9/2004 12:11:51 AM]
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Document 2 Structural Studies of HI
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Document Page 108 mulate during tre
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Page 541 and 542: Document 17 Structure and Functiona
Page 543 and 544: Document Table 1 Approval Indicatio
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Page 591 and 592: Document Page 478 lished—was asso
Page 593 and 594: Document VI. Conclusion Page 480 It
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Document D ddI, 152 tumour necrosis
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Document antistasin peptides, 281 c
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