Identification of critical regions in mouse granulocyte-macrophage colony-stimulating factor by scanning-deletion analysis.

Shanafelt, Armen B.; Kastelein, Robert A.

doi:10.1073/pnas.86.13.4872

Cited by 56 publications

(38 citation statements)

References 25 publications

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“…4; Kinemage 3). The participation of the end of helix D in receptor binding was reported for IL-4 (Postlethwaite & Seyer, 1991; Kruse et al, 1992), IL-2 (Zurawski & Zurawski, 1988;Zurawski et al, 1990), and GM-CSF (Diederichs et al, 1991;Shanafelt et al, 1991;Walter et al, 1992a). Positive charge is conserved at positions 115 and 117 (IL-4 numbering) in IL-2 and GM-CSF, respectively, and positively charged residues are found in HGH in positions structurally equivalent to residues 121 and 126 in IL-4, but nevertheless this patch appears to be a particular feature of IL-4.…”

Section: Helix Dmentioning

confidence: 78%

“…That residue was aligned with Glu 21 in GM-CSF (Shanafelt et al, 1991). This alignment, however, does not correspond to structure-based superposition because the residue corresponding to Glu 21 is His 16, while Glu 15 in IL-4 corresponds to Gln 20 in GM-CSF and Gln 8 in IL-4 (Fig.…”

Section: Helix Amentioning

confidence: 97%

“…The involvement of these residues in receptor binding in GM-CSF has been shown in a variety of studies. Shanafelt et al (1991) have shown that Lys 20 of mouse GM-CSF is directly involved in binding to the 0 subunit of the receptor, and the nature of this residue provides species specificity. Lopez et al (1992) have shown that mutation of Glu 21 in GM-CSF lowers or abolishes biological activity of the cytokine, again postulating its importance for binding to the 0 subunit.…”

Section: Helix Amentioning

confidence: 99%

“…Altmann et al (1991) showed by proline substitution that the integrity of helix B is necessary for biological activity of murine GM-CSF, although the nature of that experiment says more about overall conformation than about specific interactions of individual residues. Shanafelt et al (1991) have shown by deletion analysis that residues from helices B and C are important for biological activity of both human and murine GM-CSF, with critical residues being Thr 78…”

Section: Helices B and Cmentioning

confidence: 99%

“…2, 3). The general importance of helix D to the biological role of GM-CSF was noted by Shanafelt et al (1991), although no specific residues were pointed out. However, specific parts of that helix were unambiguously shown to be crucial for the activity of both IL-4 and IL-2.…”

Section: Helix Dmentioning

confidence: 99%

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Hematopoietic cytokines: Similarities and differences in the structures, with implications for receptor binding

1993

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Crystal and NMR structures of helical cytokines-interleukin-4 (IL-4), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-2 (IL-2)-have been compared. Root mean square deviations in the C, coordinates for the conserved regions of the helices were 1-2 A between different cytokines, about twice the differences observed for independently determined crystal and solution structures of IL-4. Considerable similarity in amino acid sequence in the areas expected to interact with the receptors was detected, and the available mutagenesis data for these cytokines were correlated with structure conservation. Models of cytokine-receptor interactions were postulated for IL-4 based on its structure as well as on the published structure of human growth hormone interacting with its receptors (de Vos, A.M., Ultsch, M., & Kossiakoff, A.A., 1992, Science 255, 306-312). Patches of positively charged residues on the surfaces of helices C and D of IL-4 may be responsible for the interactions with the negatively charged residues found in the complementary parts of the IL-4 receptors.

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Section: Helix Dmentioning

confidence: 78%

Section: Helix Amentioning

confidence: 97%

Section: Helix Amentioning

confidence: 99%

Section: Helices B and Cmentioning

confidence: 99%

Section: Helix Dmentioning

confidence: 99%

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Hematopoietic cytokines: Similarities and differences in the structures, with implications for receptor binding

1993

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Design, synthesis and conformational analysis of hGM-CSF[13-31]-Gly-Pro-Gly-[103-116]

Noli

Gurrath

Rovero³

et al. 1997

J. Peptide Sci.

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On the basis of the X-ray structure and results from structure-activity relationship studies, the following GM-CSF analogue was designed and synthesized by solid-phase methodology: hGM-CSF[13-31]-Gly-Pro-Gly-[103-116]-NH2. This analogue was constructed to comprise helices A and D of the native hGM-CSF, covalently linked in an antiparallel orientation by the tripeptide spacer Gly-Pro-Gly, which is known as a turn-inducing sequence. The conformational analysis of the analogue by CD spectroscopy revealed an essentially random structure in water, while alpha-helix formation was observed upon addition of TFE. In 40% TFE the helix content was approximately 45%. By two-dimensional NMR experiments in 1:1 water/trifluoroethanol mixture two helical sequences were identified comprising the segments corresponding to helix A and helix D. In addition to medium-range NOESY connectivities, a long-range cross-peak was found involving the leucine residues at positions 13 and 35. Based on the experimentally derived data (54 NOEs), the structure was refined by restrained molecular dynamics simulations over 120 ps at various temperatures. A representative conformation derived from the computer simulation is mainly characterized by two helical segments connected by a loop region. The overall three-dimensional structure of the analogue is comparable to the X-ray structure of hGM-CSF in that helices A and D are oriented in an antiparallel fashion, forming a two alpha-helix bundle. Nevertheless, there are small differences in the topology of the helices between the solution structure of the designed analogue and the X-ray structure of hGM-CSF. The possible implications of these conformational features at the effects of biological activity are discussed.

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The amino-terminal helix of GM-CSF and IL-5 governs high affinity binding to their receptors.

et al. 1991

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Transduction of the biological effects of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) and interleukin‐5 (IL‐5) requires the interaction of each cytokine with at least two cell surface receptor components, one of which is shared between these two cytokines. A strategy is presented that allowed us to identify receptor binding determinants in GM‐CSF and IL‐5. Mixed species (human and mouse) receptors were used to locate unique receptor binding domains on a series of human‐mouse hybrid GM‐CSF and IL‐5 cytokines. Results show that the interaction of these two cytokines with the shared subunit of their high affinity receptor complexes is governed by a very small part of their peptide chains. The presence of a few key residues in the amino‐terminal alpha‐helix of each ligand is sufficient to confer specificity to the interaction. Comparison with other cytokines suggests that the amino‐terminal helix of many of these proteins may contain the recognition element for the formation of high affinity binding sites with the alpha subunit of their multi‐component receptors.

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Identification of critical regions in mouse granulocyte-macrophage colony-stimulating factor by scanning-deletion analysis.

Cited by 56 publications

References 25 publications

Hematopoietic cytokines: Similarities and differences in the structures, with implications for receptor binding

Hematopoietic cytokines: Similarities and differences in the structures, with implications for receptor binding

Design, synthesis and conformational analysis of hGM-CSF[13-31]-Gly-Pro-Gly-[103-116]

The amino-terminal helix of GM-CSF and IL-5 governs high affinity binding to their receptors.

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