The WSXWS motif in cytokine receptors is a molecular switch involved in receptor activation: insight from structures of the prolactin receptor - PubMed (original) (raw)

. 2012 Feb 8;20(2):270-82.

doi: 10.1016/j.str.2011.12.010.

Affiliations

• PMID: 22325776
• DOI: 10.1016/j.str.2011.12.010

Free article

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

Robert Dagil et al. Structure. 2012.

Free article

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.

Copyright © 2012 Elsevier Ltd. All rights reserved.

PubMed Disclaimer

Similar articles

• Structural characterization of the stem-stem dimerization interface between prolactin receptor chains complexed with the natural hormone.
  van Agthoven J, Zhang C, Tallet E, Raynal B, Hoos S, Baron B, England P, Goffin V, Broutin I. van Agthoven J, et al. J Mol Biol. 2010 Nov 19;404(1):112-26. doi: 10.1016/j.jmb.2010.09.036. Epub 2010 Sep 25. J Mol Biol. 2010. PMID: 20875426
• Solution structure of human prolactin.
  Teilum K, Hoch JC, Goffin V, Kinet S, Martial JA, Kragelund BB. Teilum K, et al. J Mol Biol. 2005 Aug 26;351(4):810-23. doi: 10.1016/j.jmb.2005.06.042. J Mol Biol. 2005. PMID: 16045928
• Template-based docking of a prolactin receptor proline-rich motif octapeptide to FKBP12: implications for cytokine receptor signaling.
  Soman KV, Hanks BA, Tien H, Chari MV, O'Neal KD, Morrisett JD. Soman KV, et al. Protein Sci. 1997 May;6(5):999-1008. doi: 10.1002/pro.5560060505. Protein Sci. 1997. PMID: 9144770 Free PMC article.
• Beyond dimerization: a membrane-dependent activation model for interleukin-4 receptor-mediated signalling.
  Weidemann T, Höfinger S, Müller K, Auer M. Weidemann T, et al. J Mol Biol. 2007 Mar 9;366(5):1365-73. doi: 10.1016/j.jmb.2006.11.095. Epub 2006 Dec 6. J Mol Biol. 2007. PMID: 17223132 Review.
• The structural basis for biological signaling, regulation, and specificity in the growth hormone-prolactin system of hormones and receptors.
  Kossiakoff AA. Kossiakoff AA. Adv Protein Chem. 2004;68:147-69. doi: 10.1016/S0065-3233(04)68005-3. Adv Protein Chem. 2004. PMID: 15500861 Review.

Cited by

• A conserved sugar bridge connected to the WSXWS motif has an important role for transport of IL-21R to the plasma membrane.
  Siupka P, Hamming OT, Kang L, Gad HH, Hartmann R. Siupka P, et al. Genes Immun. 2015 Sep;16(6):405-13. doi: 10.1038/gene.2015.22. Epub 2015 Jun 4. Genes Immun. 2015. PMID: 26043171
• In silico analyses of leptin and leptin receptor of spotted snakehead Channa punctata.
  Bakshi A, Rai U. Bakshi A, et al. PLoS One. 2022 Jul 7;17(7):e0270881. doi: 10.1371/journal.pone.0270881. eCollection 2022. PLoS One. 2022. PMID: 35797380 Free PMC article.
• The structure of the extracellular domains of human interleukin 11α receptor reveals mechanisms of cytokine engagement.
  Metcalfe RD, Aizel K, Zlatic CO, Nguyen PM, Morton CJ, Lio DS, Cheng HC, Dobson RCJ, Parker MW, Gooley PR, Putoczki TL, Griffin MDW. Metcalfe RD, et al. J Biol Chem. 2020 Jun 12;295(24):8285-8301. doi: 10.1074/jbc.RA119.012351. Epub 2020 Apr 24. J Biol Chem. 2020. PMID: 32332100 Free PMC article.
• Phosphorylation of Schizosaccharomyces pombe Dss1 mediates direct binding to the ubiquitin-ligase Dma1 in vitro.
  Jacobsen NL, Bloch M, Millard PS, Ruidiaz SF, Elsborg JD, Boomsma W, Hendus-Altenburger R, Hartmann-Petersen R, Kragelund BB. Jacobsen NL, et al. Protein Sci. 2023 Sep;32(9):e4733. doi: 10.1002/pro.4733. Protein Sci. 2023. PMID: 37463013 Free PMC article.
• Validation is a dish oft served cold.
  Wilson DB. Wilson DB. Blood. 2014 Jun 12;123(24):3688-9. doi: 10.1182/blood-2014-05-572925. Blood. 2014. PMID: 24926068 Free PMC article.

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Elsevier Science

• Other Literature Sources

  • The Lens - Patent Citations Database

• Molecular Biology Databases

  • BioCyc
  • Gene Ontology
  • IMEx Consortium