Receptor-mediated dimerization of JAK2 FERM domains is required for JAK2 activation

Abstract
Data availability
Article and author information
Metrics

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

(2018) Coordinates and structure factors for JAK2/EPOR
. Publicly available at the RCSB Protein Data Bank (accession no. 6E2Q).

http://www.rcsb.org/pdb/results/results.do?tabtoshow=Unreleased&qrid=8067DC03
(2018) Coordinates and structure factors for JAK2/LEPR
. Publicly available at the RCSB Protein Data Bank (accession no. 6E2P).

http://www.rcsb.org/pdb/search/structidSearch.do?structureId=6E2P

Article and author information

Author details

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..
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..
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..

"This ORCID iD identifies the author of this article:" 0000-0002-8662-074X

Funding

No external funding was received for this work.

Copyright

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.