Enhancement of cell type specificity by quantitative modulation of a chimeric ligand.

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Cironi P, Swinburne IA, Silver PA

Enhancement of cell type specificity by quantitative modulation of a chimeric ligand.

J Biol Chem. 2008 Mar 28;283(13):8469-76. doi: 10.1074/jbc.M708502200. Epub 2008 Jan 29.

PubMed ID
18230610 [ View in PubMed
]
Abstract

Evolution modulates the quantitative characteristics of protein interactions and often uses combinations of weak interactions to achieve a particular specificity. We addressed how quantitative optimization might be used in the design of multidomain proteins, using a chimera containing epidermal growth factor (EGF) as a cell targeting element and interferon-alpha-2a (IFNalpha-2a) to initiate signal transduction. We first connected EGF and IFNalpha-2a via a linker that allows both ligands to bind to their receptors on a cell surface and then incorporated a series of mutations into the IFNalpha-2a portion that progressively decrease both the on rate and the dissociation constant of the IFNalpha-2a-IFNalpha receptor 2 (IFNAR2) interaction. Using this strategy, we designed chimeric proteins in which the activation of the IFNalpha receptor in HeLa, A431, and engineered Daudi cells depends on the presence of EGF receptor on the same cell. The mutant chimeric proteins also inhibited proliferation of IFNalpha-sensitive cells in an EGF receptor-dependent manner. These results provide insights into the quantitative requirements for specific binding to multisubunit receptors and illustrate the value of a quantitative approach in the design of synthetic-biological constructs.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
Interferon alfa-2aInterferon alpha/beta receptor 1ProteinHumans
Yes
Not AvailableDetails
Interferon alfa-2aInterferon alpha/beta receptor 2ProteinHumans
Yes
Not AvailableDetails