TY - JOUR
T1 - The WSXWS motif in cytokine receptors is a molecular switch involved in receptor activation
T2 - insight from structures of the prolactin receptor
AU - Dagil, Robert
AU - Knudsen, Maiken J.
AU - Olsen, Johan Gotthardt
AU - O'Shea, Charlotte
AU - Franzmann, Magnus
AU - Goffin, Vincent
AU - Teilum, Kaare
AU - Breinholt, Jens
AU - Kragelund, Birthe Brandt
N1 - Copyright © 2012 Elsevier Ltd. All rights reserved.
PY - 2012/2/8
Y1 - 2012/2/8
N2 - 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.
AB - 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.
U2 - 10.1016/j.str.2011.12.010
DO - 10.1016/j.str.2011.12.010
M3 - Journal article
C2 - 22325776
SN - 0969-2126
VL - 20
SP - 270
EP - 282
JO - Structure
JF - Structure
IS - 2
ER -
