Structural requirements of the extracellular to transmembrane domain junction for erythropoietin receptor function
(2005) Journal of Biological Chemistry — Vol. 280, n° 15, p. 14844-14854 (2005)
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- Abstract
- The erythropoietin receptor (EpoR) is crucial for erythrocyte formation. The x-ray crystal structures of the EpoR extracellular domain lack the juxtamembrane (JM) region and the junction to the transmembrane (TM) domain. Yet the JM-TM regions are important for transmitting the conformational change imposed on the receptor dimer by Epo binding. Cysteine-scanning mutagenesis of the JM-TM regions identified three novel constitutively active mutants, demonstrating close disulfide-bonded juxtapositioning of these residues in the JM (L223C) and N-terminal TM domain (L226C, I227C). Chemical cross-linking defined the interface of the active helical TM dimer and revealed that the JM-TM segment encompassing Leu(226)-Leu(230) is non-helical. Molecular dynamics and NMR studies indicated that the TM-JM junction forms an N-terminal helix cap. This structure is important for EpoR function because replacement of this motif by consecutive leucines rendered the receptor constitutively active.
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Kubatzky, K., Liu, W., Goldgraben, K., Simmerling, C., Smith, S., & Constantinescu, S. (2005). Structural requirements of the extracellular to transmembrane domain junction for erythropoietin receptor function. Journal of Biological Chemistry, 280(15), 14844-14854. https://doi.org/10.1074/jbc.M411251200 (Original work published 2005)