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

Robert Dagil; Maiken J. Knudsen; Johan Gotthardt Olsen; Charlotte O'Shea; Magnus Franzmann; Vincent Goffin; Kaare Teilum; Jens Breinholt; Birthe Brandt Kragelund

doi:10.1016/j.str.2011.12.010

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

Robert Dagil, Maiken J. Knudsen, Johan Gotthardt Olsen, Charlotte O'Shea, Magnus Franzmann, Vincent Goffin, Kaare Teilum, Jens Breinholt, Birthe Brandt Kragelund

45 Citations (Scopus)

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.

Original language	English
Journal	Structure
Volume	20
Issue number	2
Pages (from-to)	270-282
Number of pages	13
ISSN	0969-2126
DOIs	https://doi.org/10.1016/j.str.2011.12.010
Publication status	Published - 8 Feb 2012

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

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.",

author = "Robert Dagil and Knudsen, {Maiken J.} and Olsen, {Johan Gotthardt} and Charlotte O'Shea and Magnus Franzmann and Vincent Goffin and Kaare Teilum and Jens Breinholt and Kragelund, {Birthe Brandt}",

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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

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.

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DO - 10.1016/j.str.2011.12.010

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EP - 282

JO - Structure

JF - Structure

IS - 2

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

Abstract

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