CONVERSION OF THE BIOLOGICAL SPECIFICITY OF MURINE TO HUMAN LEUKEMIA INHIBITORY FACTOR BY REPLACING 6 AMINO-ACID-RESIDUES

Layton, MJ; Owczarek, CM; Metcalf, D; CLARK, RL; Smith, DK; Treutlein, HR; Nicola, NA

Author(s): Layton, MJ; Owczarek, CM; Metcalf, D; CLARK, RL; Smith, DK; Treutlein, HR; Nicola, NA;
Details: Publication Year 1994-11-25,Volume 269,Issue #47,Page 29891-29896
Journal Title: JOURNAL OF BIOLOGICAL CHEMISTRY
Publication Type: Journal Article
Abstract: Mouse and human leukemia inhibitory factor (mLIF and hLIF) have similar to 80% amino acid identity, but mLIF cannot bind to the hLIF receptor (hLIF-R), while hLIF binds to the cw-chain of the mLIF receptor (mLIF-R) with a much higher affinity than does mLIF. We have previously shown that the same regions confer both these properties of hLIF and map to an area within the predicted third alpha-helix and two of the loops of hLIF (Owczarek, C. M., Layton, M. J., Metcalf, D., Lock, P., Willson, T. A., Gough, N. M., and Nicola, N. A. (1993) EMBO J. 12, 3487-3495). The present studies, using interspecies chimeras of mLIF and hLIF have defined 6 residues (Asp(57), Ser(107), His(112), Ser(113), Val(155), and Lys(158)) that contribute most of the binding energy involved in the interaction of hLIF and the hLIF-R alpha-chain, and form a surface at one end of the predicted four alpha-helical bundle of the hLIF molecule. Mouse LIF is unable to bind to the hLIF-R alpha-chain or activate the cellular hLIF-R, but when these 6 residues were substituted onto an mLIF framework, they were able to reconstitute both the binding and biological activities specific to hLIF.
Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Keywords: COLONY-STIMULATING FACTOR; IL-6 SIGNAL TRANSDUCER; HUMAN GROWTH-HORMONE; HUMAN INTERLEUKIN-4; CRYSTAL-STRUCTURE; ONCOSTATIN-M; RECEPTOR; BINDING; CELLS; MUTAGENESIS
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Creation Date: 1994-11-25 12:00:00