Crystal Structure of the FERM-SH2 Module of Human Jak2

McNally, Randall; Toms, Angela V.; Eck, Michael J.; Boggon, Titus J.

doi:10.1371/journal.pone.0156218

Crystal Structure of the FERM-SH2 Module of Human Jak2

Journal Article · Thu May 26 00:00:00 EDT 2016 · PLoS ONE

DOI:https://doi.org/10.1371/journal.pone.0156218· OSTI ID:1274764

McNally, Randall ^[1]; Toms, Angela V. ^[2]; Eck, Michael J. ^[1]; Boggon, Titus J. ^[3]

Dana-Farber Cancer Inst., Boston, MA (United States); Harvard Medical School, Boston, MA (United States)
Forma Therapeutics, Watertown, MA (United States); Dana-Farber Cancer Inst., Boston, MA (United States); Harvard Medical School, Boston, MA (United States)
Yale Univ. School of Medicine, New Haven, CT (United States)

Jak-family tyrosine kinases mediate signaling from diverse cytokine receptors. Binding of Jaks to their cognate receptors is mediated by their N-terminal region, which contains FERM and SH2 domains. Here we describe the crystal structure of the FERM-SH2 region of Jak2 at 3.0Å resolution. The structure reveals that these domains and their flanking linker segments interact intimately to form an integrated structural module. The Jak2 FERM-SH2 structure closely resembles that recently described for Tyk2, another member of the Jak family. While the overall architecture and interdomain orientations are preserved between Jak2 and Tyk2, we identify residues in the putative receptor-binding groove that differ between the two and may contribute to the specificity of receptor recognition. Analysis of Jak mutations that are reported to disrupt receptor binding reveals that they lie in the hydrophobic core of the FERM domain, and are thus expected to compromise the structural integrity of the FERM-SH2 unit. Similarly, analysis of mutations in Jak3 that are associated with severe combined immunodeficiency suggests that they compromise Jak3 function by destabilizing the FERM-SH2 structure.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Inst. of Health

OSTI ID:: 1274764

Journal Information:: PLoS ONE, Journal Name: PLoS ONE Journal Issue: 5 Vol. 11; ISSN 1932-6203

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

References (59)

Molecular Modeling of the Jak3 Kinase Domains and Structural Basis for Severe Combined Immunodeficiency Vihinen, Mauno; Villa, Anna; Mella, Patrizia Clinical Immunology, Vol. 96, Issue 2 https://doi.org/10.1006/clim.2000.4880	journal	August 2000
Jaks and cytokine receptors—An intimate relationship Haan, Claude; Kreis, Stephanie; Margue, Christiane Biochemical Pharmacology, Vol. 72, Issue 11 https://doi.org/10.1016/j.bcp.2006.04.013	journal	November 2006
The JAK-STAT Pathway at Twenty Stark, George R.; Darnell, James E. Immunity, Vol. 36, Issue 4 https://doi.org/10.1016/j.immuni.2012.03.013	journal	April 2012
Inference of Macromolecular Assemblies from Crystalline State Krissinel, Evgeny; Henrick, Kim Journal of Molecular Biology, Vol. 372, Issue 3 https://doi.org/10.1016/j.jmb.2007.05.022	journal	September 2007
Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID) Macchi, Paolo; Villa, Anna; Giliani, Silvia Nature, Vol. 377, Issue 6544 https://doi.org/10.1038/377065a0	journal	September 1995
The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling Ungureanu, Daniela; Wu, Jinhua; Pekkala, Tuija Nature Structural & Molecular Biology, Vol. 18, Issue 9 https://doi.org/10.1038/nsmb.2099	journal	August 2011
Structure of a pseudokinase-domain switch that controls oncogenic activation of Jak kinases Toms, Angela V.; Deshpande, Anagha; McNally, Randall Nature Structural & Molecular Biology, Vol. 20, Issue 10 https://doi.org/10.1038/nsmb.2673	journal	September 2013
Structural basis of recognition of interferon-α receptor by tyrosine kinase 2 Wallweber, Heidi J. A.; Tam, Christine; Franke, Yvonne Nature Structural & Molecular Biology, Vol. 21, Issue 5 https://doi.org/10.1038/nsmb.2807	journal	April 2014
JAK–cytokine receptor recognition, unboxed McNally, Randall; Eck, Michael J. Nature Structural & Molecular Biology, Vol. 21, Issue 5 https://doi.org/10.1038/nsmb.2824	journal	May 2014
Molecular basis for pseudokinase-dependent autoinhibition of JAK2 tyrosine kinase Shan, Yibing; Gnanasambandan, Kavitha; Ungureanu, Daniela Nature Structural & Molecular Biology, Vol. 21, Issue 7 https://doi.org/10.1038/nsmb.2849	journal	June 2014
Receptor specific downregulation of cytokine signaling by autophosphorylation in the FERM domain of Jak2 Funakoshi-Tago, Megumi; Pelletier, Stephane; Matsuda, Tadashi The EMBO Journal, Vol. 25, Issue 20 https://doi.org/10.1038/sj.emboj.7601365	journal	October 2006
Hematopoietic cytokine receptor signaling Baker, S. J.; Rane, S. G.; Reddy, E. P. Oncogene, Vol. 26, Issue 47 https://doi.org/10.1038/sj.onc.1210757	journal	October 2007
A regulating role of the JAK2 FERM domain in hyperactivation of JAK2(V617F) Zhao, Lequn; Ma, Yue; Seemann, Joachim Biochemical Journal, Vol. 426, Issue 1 https://doi.org/10.1042/bj20090615	journal	January 2010
Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition Lupardus, P. J.; Ultsch, M.; Wallweber, H. Proceedings of the National Academy of Sciences, Vol. 111, Issue 22 https://doi.org/10.1073/pnas.1401180111	journal	May 2014
Critical cytoplasmic region of the interleukin 6 signal transducer gp130 is conserved in the cytokine receptor family. Murakami, M.; Narazaki, M.; Hibi, M. Proceedings of the National Academy of Sciences, Vol. 88, Issue 24 https://doi.org/10.1073/pnas.88.24.11349	journal	December 1991
Mapping of a Region within the N Terminus of Jak1 Involved in Cytokine Receptor Interaction Haan, Claude; Is'harc, Hayaatun; Hermanns, Heike M. Journal of Biological Chemistry, Vol. 276, Issue 40 https://doi.org/10.1074/jbc.m106135200	journal	July 2001
The Jak1 SH2 Domain Does Not Fulfill a Classical SH2 Function in Jak/STAT Signaling but Plays a Structural Role for Receptor Interaction and Up-regulation of Receptor Surface Expression Radtke, Simone; Haan, Serge; Jörissen, Angela Journal of Biological Chemistry, Vol. 280, Issue 27 https://doi.org/10.1074/jbc.m500822200	journal	May 2005
Structural basis of the membrane-targeting and unmasking mechanisms of the radixin FERM domain Hamada, K. The EMBO Journal, Vol. 19, Issue 17 https://doi.org/10.1093/emboj/19.17.4449	journal	September 2000
Dali server: conservation mapping in 3D Holm, Liisa; Rosenstrï¿½m, Pï¿½ivi Nucleic Acids Research, Vol. 38, Issue suppl_2 https://doi.org/10.1093/nar/gkq366	journal	May 2010
Genetics of Myeloproliferative Neoplasms Viny, Aaron D.; Levine, Ross L. The Cancer Journal, Vol. 20, Issue 1 https://doi.org/10.1097/ppo.0000000000000013	journal	January 2014
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/s0021889807021206	journal	July 2007
Secondary-structure matching (SSM), a new tool for fast protein structure alignment in three dimensions Krissinel, E.; Henrick, K. Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12 https://doi.org/10.1107/s0907444904026460	journal	November 2004
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/s0907444909047337	journal	January 2010
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/s0907444910007493	journal	March 2010
Overview of the CCP 4 suite and current developments Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/s0907444910045749	journal	March 2011
Janus kinases in immune cell signaling Ghoreschi, Kamran; Laurence, Arian; O’Shea, John J. Immunological Reviews, Vol. 228, Issue 1 https://doi.org/10.1111/j.1600-065x.2008.00754.x	journal	March 2009
Mutation of Jak3 in a Patient with SCID: Essential Role of Jak3 in Lymphoid Development Russell, S. M.; Tayebi, N.; Nakajima, H. Science, Vol. 270, Issue 5237 https://doi.org/10.1126/science.270.5237.797	journal	November 1995
Jak3-Independent Trafficking of the Common γ Chain Receptor Subunit: Chaperone Function of Jaks Revisited Hofmann, Sigrun R.; Lam, Albert Q.; Frank, Stephan Molecular and Cellular Biology, Vol. 24, Issue 11 https://doi.org/10.1128/mcb.24.11.5039-5049.2004	journal	June 2004
Modular Peptide Recognition Domains in Eukaryotic Signaling Kuriyan, John; Cowburn, David Annual Review of Biophysics and Biomolecular Structure, Vol. 26, Issue 1 https://doi.org/10.1146/annurev.biophys.26.1.259	journal	June 1997
Oncogenic JAK2V617F requires an intact SH2-like domain for constitutive activation and induction of a myeloproliferative disease in mice Gorantla, Sivahari P.; Dechow, Tobias N.; Grundler, Rebekka Blood, Vol. 116, Issue 22 https://doi.org/10.1182/blood-2009-07-236133	journal	November 2010
SRC Homology 2 Domain Binding Sites in Insulin, IGF-1 and FGF receptor mediated signaling networks reveal an extensive potential interactome Liu, Bernard A.; Engelmann, Brett W.; Jablonowski, Karl Cell Communication and Signaling, Vol. 10, Issue 1 https://doi.org/10.1186/1478-811x-10-27	journal	January 2012
PHENIX: a comprehensive Python-based system for macromolecular structure solution. Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.45787	text	January 2010
Dual Role of the Jak1 FERM and Kinase Domains in Cytokine Receptor Binding and in Stimulation-Dependent Jak Activation Haan, Serge; Margue, Christiane; Engrand, Arnaud The Journal of Immunology, Vol. 180, Issue 2 https://doi.org/10.4049/jimmunol.180.2.998	journal	January 2008
Mutations in severe combined immune deficiency (SCID) due to JAK3 deficiency Notarangelo, Luigi D.; Mella, Patrizia; Jones, Alison Human Mutation, Vol. 18, Issue 4 https://doi.org/10.1002/humu.1188	journal	October 2001
Structure of the ERM Protein Moesin Reveals the FERM Domain Fold Masked by an Extended Actin Binding Tail Domain Pearson, Matthew A.; Reczek, David; Bretscher, Anthony Cell, Vol. 101, Issue 3 https://doi.org/10.1016/S0092-8674(00)80836-3	journal	April 2000
Unexpected Effects of FERM Domain Mutations on Catalytic Activity of Jak3 Zhou, Yong-Jie; Chen, Min; Cusack, Nancy A. Molecular Cell, Vol. 8, Issue 5 https://doi.org/10.1016/S1097-2765(01)00398-7	journal	November 2001
Structural Snapshots of Full-Length Jak1, a Transmembrane gp130/IL-6/IL-6Rα Cytokine Receptor Complex, and the Receptor-Jak1 Holocomplex Lupardus, Patrick J.; Skiniotis, Georgios; Rice, Amanda J. Structure, Vol. 19, Issue 1 https://doi.org/10.1016/j.str.2010.10.010	journal	January 2011
Phosphorylation Reaction in cAPK Protein Kinase-Free Energy Quantum Mechanical/Molecular Mechanics Simulations Valiev, Marat; Yang, Jie; Adams, Joseph A. The Journal of Physical Chemistry B, Vol. 111, Issue 47 https://doi.org/10.1021/jp074853q	journal	November 2007
Recognition of a high-affinity phosphotyrosyl peptide by the Src homology-2 domain of p56lck Eck, Michael J.; Shoelson, Steven E.; Harrison, Stephen C. Nature, Vol. 362, Issue 6415 https://doi.org/10.1038/362087a0	journal	March 1993
A regulating role of the JAK2 FERM domain in hyperactivation of JAK2(V617F) Zhao, Lequn; Ma, Yue; Seemann, Joachim Biochemical Journal, Vol. 426, Issue 1 https://doi.org/10.1042/BJ20090615	journal	January 2010
Mapping of a Region within the N Terminus of Jak1 Involved in Cytokine Receptor Interaction Haan, Claude; Is'harc, Hayaatun; Hermanns, Heike M. Journal of Biological Chemistry, Vol. 276, Issue 40 https://doi.org/10.1074/jbc.M106135200	journal	July 2001
Janus Kinase (Jak) Subcellular Localization Revisited: THE EXCLUSIVE MEMBRANE LOCALIZATION OF ENDOGENOUS JANUS KINASE 1 BY CYTOKINE RECEPTOR INTERACTION UNCOVERS THE Jak·RECEPTOR COMPLEX TO BE EQUIVALENT TO A RECEPTOR TYROSINE KINASE Behrmann, Iris; Smyczek, Tanja; Heinrich, Peter C. Journal of Biological Chemistry, Vol. 279, Issue 34 https://doi.org/10.1074/jbc.M404202200	journal	May 2004
The Jak1 SH2 Domain Does Not Fulfill a Classical SH2 Function in Jak/STAT Signaling but Plays a Structural Role for Receptor Interaction and Up-regulation of Receptor Surface Expression Radtke, Simone; Haan, Serge; Jörissen, Angela Journal of Biological Chemistry, Vol. 280, Issue 27 https://doi.org/10.1074/jbc.M500822200	journal	May 2005
Janus Kinases Affect Thrombopoietin Receptor Cell Surface Localization and Stability Royer, Yohan; Staerk, Judith; Costuleanu, Marcel Journal of Biological Chemistry, Vol. 280, Issue 29 https://doi.org/10.1074/jbc.M501376200	journal	May 2005
Autosomal SCID caused by a point mutation in the N-terminus of Jak3: mapping of the Jak3-receptor interaction domain Cacalano, N. A. The EMBO Journal, Vol. 18, Issue 6 https://doi.org/10.1093/emboj/18.6.1549	journal	March 1999
ConSurf 2010: calculating evolutionary conservation in sequence and structure of proteins and nucleic acids Ashkenazy, H.; Erez, E.; Martz, E. Nucleic Acids Research, Vol. 38, Issue Web Server https://doi.org/10.1093/nar/gkq399	journal	May 2010
Genetics of Myeloproliferative Neoplasms Viny, Aaron D.; Levine, Ross L. The Cancer Journal, Vol. 20, Issue 1 https://doi.org/10.1097/PPO.0000000000000013	journal	January 2014
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
Secondary-structure matching (SSM), a new tool for fast protein structure alignment in three dimensions Krissinel, E.; Henrick, K. Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12 https://doi.org/10.1107/S0907444904026460	journal	November 2004
Scaling and assessment of data quality Evans, Philip Acta Crystallographica Section D Biological Crystallography, Vol. 62, Issue 1, p. 72-82 https://doi.org/10.1107/S0907444905036693	journal	December 2005
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
Overview of the CCP 4 suite and current developments Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444910045749	journal	March 2011
Janus kinases in immune cell signaling Ghoreschi, Kamran; Laurence, Arian; O’Shea, John J. Immunological Reviews, Vol. 228, Issue 1 https://doi.org/10.1111/j.1600-065X.2008.00754.x	journal	March 2009
Jak3-Independent Trafficking of the Common γ Chain Receptor Subunit: Chaperone Function of Jaks Revisited Hofmann, Sigrun R.; Lam, Albert Q.; Frank, Stephan Molecular and Cellular Biology, Vol. 24, Issue 11 https://doi.org/10.1128/MCB.24.11.5039-5049.2004	journal	June 2004
The Jak2V617F oncogene associated with myeloproliferative diseases requires a functional FERM domain for transformation and for expression of the Myc and Pim proto-oncogenes Wernig, Gerlinde; Gonneville, Jeffrey R.; Crowley, Brian J. Blood, Vol. 111, Issue 7 https://doi.org/10.1182/blood-2007-07-102186	journal	April 2008
Structural and Functional Basis for JAK3-Deficient Severe Combined Immunodeficiency Candotti, Fabio; Oakes, Scott A.; Johnston, James A. Blood, Vol. 90, Issue 10 https://doi.org/10.1182/blood.V90.10.3996	journal	November 1997
SRC Homology 2 Domain Binding Sites in Insulin, IGF-1 and FGF receptor mediated signaling networks reveal an extensive potential interactome Liu, Bernard A.; Engelmann, Brett W.; Jablonowski, Karl Cell Communication and Signaling, Vol. 10, Issue 1 https://doi.org/10.1186/1478-811X-10-27	journal	January 2012

Cited By (12)

The Janus Kinase (JAK) FERM and SH2 Domains: Bringing Specificity to JAK–Receptor Interactions Ferrao, Ryan; Lupardus, Patrick J. Frontiers in Endocrinology, Vol. 8 https://doi.org/10.3389/fendo.2017.00071	journal	April 2017
The Growth Hormone Receptor: Mechanism of Receptor Activation, Cell Signaling, and Physiological Aspects Dehkhoda, Farhad; Lee, Christine M. M.; Medina, Johan Frontiers in Endocrinology, Vol. 9 https://doi.org/10.3389/fendo.2018.00035	journal	February 2018
Parthenolide Inhibits STAT3 Signaling by Covalently Targeting Janus Kinases Liu, Man; Xiao, Chengqian; Sun, Mingwei Molecules, Vol. 23, Issue 6 https://doi.org/10.3390/molecules23061478	journal	June 2018
Are peptides a solution for the treatment of hyperactivated JAK3 pathways? Dullius, Anja; Rocha, Claudia Monfroni; Laufer, Stefan Inflammopharmacology, Vol. 27, Issue 3 https://doi.org/10.1007/s10787-019-00589-2	journal	March 2019
Erratum: Rethinking JAK2 inhibition: towards novel strategies of more specific and versatile Janus kinase inhibition Leroy, E.; Constantinescu, S. N. Leukemia, Vol. 31, Issue 12 https://doi.org/10.1038/leu.2017.158	journal	December 2017
Rethinking JAK2 inhibition: towards novel strategies of more specific and versatile janus kinase inhibition Leroy, E.; Constantinescu, S. N. Leukemia, Vol. 31, Issue 5 https://doi.org/10.1038/leu.2017.43	journal	January 2017
Xanthatin inhibits STAT3 and NF‐κB signalling by covalently binding to JAK and IKK kinases Liu, Man; Xiao, Cheng‐qian; Sun, Ming‐wei Journal of Cellular and Molecular Medicine, Vol. 23, Issue 6 https://doi.org/10.1111/jcmm.14322	journal	April 2019
Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations Wilmes, Stephan; Hafer, Maximillian; Vuorio, Joni Science, Vol. 367, Issue 6478 https://doi.org/10.1126/science.aaw3242	journal	February 2020
Phosphorylation of Janus kinase 1 (JAK1) by AMP-activated protein kinase (AMPK) links energy sensing to anti-inflammatory signaling Rutherford, C.; Speirs, C.; Williams, J. J. L. Science Signaling, Vol. 9, Issue 453 https://doi.org/10.1126/scisignal.aaf8566	journal	November 2016
Mechanistic Insights into Regulation of JAK2 Tyrosine Kinase Hubbard, Stevan R. Frontiers in Endocrinology, Vol. 8 https://doi.org/10.3389/fendo.2017.00361	journal	January 2018
Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations Wilmes, Stephan; Hafer, Maximillian; Vuorio, Joni Zenodo https://doi.org/10.5281/zenodo.3555290	text	January 2019
Receptor-mediated dimerization of JAK2 FERM domains is required for JAK2 activation Ferrao, Ryan D.; Wallweber, Heidi JA; Lupardus, Patrick J. eLife, Vol. 7 https://doi.org/10.7554/elife.38089	journal	July 2018

Similar Records

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

Journal Article · Wed Jul 25 00:00:00 EDT 2018 · eLife · OSTI ID:1628888

Crystal Structure of the FERM Domain of Focal Adhesion Kinase

Journal Article · Sat Dec 31 23:00:00 EST 2005 · J. Biol. Chem. · OSTI ID:914144

The Janus kinase family and signaling through members of the cytokine receptor superfamily

Journal Article · Fri Dec 30 23:00:00 EST 1994 · Proceedings of the Society for Experimental Biology and Medicine · OSTI ID:466623

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
SH2 domains
crystal structure
cytokine receptors
hydrogen bonding
molecular structure
point mutation
salt bridges
tyrosine kinases

Crystal Structure of the FERM-SH2 Module of Human Jak2

Citation Formats

References (59)

Cited By (12)

Similar Records

Related Subjects