The WSXWS motif in cytokine receptors is a molecular switch involved in receptor activation: insight from structures of the prolactin receptor

Structure. 2012 Feb 8;20(2):270-82. doi: 10.1016/j.str.2011.12.010.

Abstract

The prolactin receptor (PRLR) is activated by binding of prolactin in a 2:1 complex, but the activation mechanism is poorly understood. PRLR has a conserved WSXWS motif generic to cytokine class I receptors. We have determined the nuclear magnetic resonance solution structure of the membrane proximal domain of the human PRLR and find that the tryptophans of the motif adopt a T-stack conformation in the unbound state. By contrast, in the hormone bound state, a Trp/Arg-ladder is formed. The conformational change is hormone-dependent and influences the receptor-receptor dimerization site 3. In the constitutively active, breast cancer-related receptor mutant PRLR(I146L), we observed a stabilization of the dimeric state and a change in the dynamics of the motif. Here we demonstrate a structural link between the WSXWS motif, hormone binding, and receptor dimerization and propose it as a general mechanism for class 1 receptor activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Binding Sites
  • Circular Dichroism
  • Humans
  • Models, Molecular
  • Nuclear Magnetic Resonance, Biomolecular
  • Particle Size
  • Prolactin / chemistry
  • Protein Binding
  • Protein Structure, Quaternary
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Receptors, Cytokine / chemistry*
  • Receptors, Prolactin / chemistry*
  • Titrimetry

Substances

  • Receptors, Cytokine
  • Receptors, Prolactin
  • Prolactin

Associated data

  • PDB/2LFG