The WSXWS motif in cytokine receptors is a molecular switch involved in receptor activation: insight from structures of the prolactin receptor.
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.
Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark.
Robert
R
Dagil
Maiken J
MJ
Knudsen
Johan G
JG
Olsen
Charlotte
C
O'Shea
Magnus
M
Franzmann
Vincent
V
Goffin
Kaare
K
Teilum
Jens
J
Breinholt
Birthe B
BB
Kragelund
D020816:Amino Acid Motifs; D001665:Binding Sites; D002942:Circular Dichroism; D006801:Humans; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D010316:Particle Size; D011388:Prolactin / Q000737:chemistry; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D018121:Receptors, Cytokine / Q000737:chemistry*; D011981:Receptors, Prolactin / Q000737:chemistry*; D017186:Titrimetry
D018121:Receptors, Cytokine; D011981:Receptors, Prolactin; D011388:Prolactin