Intrinsically disordered cytoplasmic domains of two cytokine receptors mediate conserved interactions with membranes

TY - JOUR

T1 - Intrinsically disordered cytoplasmic domains of two cytokine receptors mediate conserved interactions with membranes

AU - Haxholm, Gitte Wolfsberg

AU - Nikolajsen, Louise Fletcher

AU - Olsen, Johan Gotthardt

AU - Fredsted, Jacob

AU - Larsen, Flemming Hofmann

AU - Goffin, Vincent

AU - Pedersen, Stine Helene Falsig

AU - Brooks, Andrew J

AU - Waters, Michael J

AU - Kragelund, Birthe Brandt

PY - 2015/6/15

Y1 - 2015/6/15

N2 - Class 1 cytokine receptors regulate essential biological processes through complex intracellular signalling networks. However, the structural platform for understanding their functions is currently incomplete as structure-function studies of the intracellular domains (ICDs) are critically lacking. The present study provides the first comprehensive structural characterization of any cytokine receptor ICD and demonstrates that the human prolactin (PRL) receptor (PRLR) and growth hormone receptor (GHR) ICDs are intrinsically disordered throughout their entire lengths. We show that they interact specifically with hallmark lipids of the inner plasma membrane leaflet through conserved motifs resembling immuno receptor tyrosine-based activation motifs (ITAMs). However, contrary to the observations made for ITAMs, lipid association of the PRLR and GHR ICDs was shown to be unaccompanied by changes in transient secondary structure and independent of tyrosine phosphorylation. The results of the present study provide a new structural platform for studying class 1 cytokine receptors andmay implicate the membrane as an active component regulating intracellular signalling.

AB - Class 1 cytokine receptors regulate essential biological processes through complex intracellular signalling networks. However, the structural platform for understanding their functions is currently incomplete as structure-function studies of the intracellular domains (ICDs) are critically lacking. The present study provides the first comprehensive structural characterization of any cytokine receptor ICD and demonstrates that the human prolactin (PRL) receptor (PRLR) and growth hormone receptor (GHR) ICDs are intrinsically disordered throughout their entire lengths. We show that they interact specifically with hallmark lipids of the inner plasma membrane leaflet through conserved motifs resembling immuno receptor tyrosine-based activation motifs (ITAMs). However, contrary to the observations made for ITAMs, lipid association of the PRLR and GHR ICDs was shown to be unaccompanied by changes in transient secondary structure and independent of tyrosine phosphorylation. The results of the present study provide a new structural platform for studying class 1 cytokine receptors andmay implicate the membrane as an active component regulating intracellular signalling.

U2 - 10.1042/BJ20141243

DO - 10.1042/BJ20141243

M3 - Journal article

C2 - 25846210

SN - 0264-6021

VL - 468

SP - 495

EP - 506

JO - Biochemical Journal

JF - Biochemical Journal

IS - 3

ER -