Abstract

Cytokines and interferons initiate intracellular signaling via receptor dimerization and activation of Janus kinases (JAKs). How JAKs structurally respond to changes in receptor conformation induced by ligand binding is not known. Here we present two crystal structures of the human JAK2 FERM and SH2 domains bound to Leptin receptor (LEPR) and Erythropoietin receptor (EPOR), which identify a novel dimeric conformation for JAK2. This 2:2 JAK2/receptor dimer, observed in both structures, identifies a previously uncharacterized receptor interaction essential to dimer formation that is mediated by a membrane-proximal peptide motif called the 'switch' region. Mutation of the receptor switch region disrupts STAT phosphorylation but does not affect JAK2 binding, indicating that receptor-mediated formation of the JAK2 FERM dimer is required for kinase activation. These data uncover the structural and molecular basis for how a cytokine-bound active receptor dimer brings together two JAK2 molecules to stimulate JAK2 kinase activity.

Data availability

Coordinates and structure factors have been deposited into the RCSB database as PDB ID 6E2Q (JAK2/EPOR) and PDB ID 6E2P (JAK2/LEPR).

The following data sets were generated

Article and author information

Author details

  1. Ryan D Ferrao

    Department of Structural Biology, Genentech Inc, South San Francisco, United States
    Competing interests
    Ryan D Ferrao, employee of Genentech, Inc. during the period when this work was performed. The author declares they have no competing interests..
  2. Heidi Wallweber

    Department of Structural Biology, Genentech Inc, South San Francisco, United States
    Competing interests
    Heidi Wallweber, employee of Genentech, Inc. during the period when this work was performed. The author declares they have no competing interests..
  3. Patrick J Lupardus

    Department of Structural Biology, Genentech Inc, South San Francisco, United States
    For correspondence
    lupardus.patrick@gene.com
    Competing interests
    Patrick J Lupardus, employee of Genentech, Inc. during the period when this work was performed. The author declares they have no competing interests..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8662-074X

Funding

No external funding was received for this work.

Reviewing Editor

  1. Yibing Shan, DE Shaw Research, United States

Version history

  1. Received: May 4, 2018
  2. Accepted: July 24, 2018
  3. Accepted Manuscript published: July 25, 2018 (version 1)
  4. Version of Record published: August 6, 2018 (version 2)

Copyright

© 2018, Ferrao et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ryan D Ferrao
  2. Heidi Wallweber
  3. Patrick J Lupardus
(2018)
Receptor-mediated dimerization of JAK2 FERM domains is required for JAK2 activation
eLife 7:e38089.
https://doi.org/10.7554/eLife.38089

Share this article

https://doi.org/10.7554/eLife.38089

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