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Protein Engineering, Vol. 12, No. 9, 771-778, September 1999
© 1999 Oxford University Press

Design, engineering and production of functional single-chain T cell receptor ligands

G.G. Burrows1,2,3,4,4, J.W. Chang1, H-P. Bächinger2,5, D.N. Bourdette1,6, H. Offner1,4,4 and A.A. Vandenbark1,3,4,4

1 Department of Neurology, 2 Department of Biochemistry and Molecular Biology and 4 Department of Molecular Microbiology and Immunology, Oregon Health Sciences University, 3 Neuroimmunology Research and 6 Neurology Service, Veterans Affairs Medical Center and 5 Shriners Hospital for Children, Portland, Oregon 97201, USA

Major histocompatibility complex (MHC) class II molecules are membrane-anchored heterodimers on the surface of antigen presenting cells (APCs) that bind the T cell receptor, initiating a cascade of interactions that results in antigen-specific activation of clonal populations of T cells. The peptide binding/T cell recognition domains of rat MHC class II (alpha-1 and beta-1 domains) were expressed as a single exon for structural and functional characterization. These recombinant single-chain T cell receptor ligands (termed `ß1{alpha}1' molecules) of approximately 200 amino acid residues were designed using the structural backbone of MHC class II molecules as template, and have been produced in Escherichia coli with and without N-terminal extensions containing antigenic peptides. Structural characterization using circular dichroism predicted that these molecules retained the antiparallel ß-sheet platform and antiparallel {alpha}-helices observed in the native MHC class II heterodimer. The proteins exhibited a cooperative two-state thermal folding–unfolding transition. ß1{alpha}1 molecules with a covalently linked MBP-72–89 peptide showed increased stability to thermal unfolding relative to the empty ß1{alpha}1 molecules. This new class of small soluble polypeptide provides a template for designing and refining human homologues useful in detecting and regulating pathogenic T cells.

Keywords: ß1{alpha}1/drug design/immunotherapy/MHC class II/TCR ligand

4 To whom correspondence should be addressed


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