PSI Structural Biology Knowledgebase

PSI | Structural Biology Knowledgebase
Header Icons
E-Collection

Related Articles
Community-Nominated Targets
July 2015
Drug Discovery: Solving the Structure of an Anti-hypertension Drug Target
July 2015
Retrospective: 7,000 Structures Closer to Understanding Biology
July 2015
Design and Evolution: Unveiling Translocator Proteins
June 2015
Signaling with DivL
May 2015
Signaling: A Platform for Opposing Functions
May 2015
Signaling: Securing Lipid-Protein Partnership
May 2015
Dynamic DnaK
March 2015
Iron-Sulfur Cluster Biosynthesis
December 2014
Mitochondrion: Flipping for UCP2
December 2014
Mitochondrion: Setting a New TRAP1
December 2014
Power in Numbers
August 2014
Quorum Sensing: A Groovy New Component
August 2014
Quorum Sensing: E. coli Gets Involved
August 2014
iTRAQing the Ubiquitinome
July 2014
Microbiome: The Dynamics of Infection
September 2013
Protein-Nucleic Acid Interaction: A Modified SAM to Modify tRNA
July 2013
Protein-Nucleic Acid Interaction: Versatile Glutamate
July 2013
PDZ Domains
April 2013
Alpha-Catenin Connections
March 2013
Cell-Cell Interaction: A FERM Connection
March 2013
Cell-Cell Interaction: Magic Structure from Microcrystals
March 2013
Cell-Cell Interaction: Modulating Self Recognition Affinity
March 2013
Bacterial Hemophores
January 2013
Archaeal Lipids
December 2012
Membrane Proteome: Capturing Multiple Conformations
December 2012
Lethal Tendencies
October 2012
Symmetry from Asymmetry
October 2012
A signal sensing switch
September 2012
Regulatory insights
September 2012
AlkB Homologs
August 2012
Budding ensemble
August 2012
Targeting Enzyme Function with Structural Genomics
July 2012
The machines behind the spindle assembly checkpoint
June 2012
Chaperone interactions
April 2012
Pilus Assembly Protein TadZ
April 2012
Revealing the Nuclear Pore Complex
March 2012
Topping off the proteasome
March 2012
Twist to open
March 2012
Disordered Proteins
February 2012
Analyzing an allergen
January 2012
Making Lipopolysaccharide
January 2012
Pulling on loose ends
January 2012
Terminal activation
December 2011
The Perils of Protein Secretion
November 2011
Bacterial Armor
October 2011
TLR4 regulation: heads or tails?
October 2011
Ribose production on demand
September 2011
Moving some metal
August 2011
Looking for lipids
July 2011
Ribofuranosyl Binding Protein
June 2011
A molecular switch for neuronal growth
May 2011
Cell wall recycler
May 2011
Added benefits
April 2011
NMR challenges current protein hydration dogma
March 2011
Nitrile Reductase QueF
March 2011
Tip formin
March 2011
Inhibiting factor
February 2011
PASK staying active
February 2011
Tryptophanyl-tRNA Synthetase
February 2011
Regulating nitrogen assimilation
January 2011
Subtle shifts
January 2011
Nitrobindin
December 2010
Function following form
October 2010
tRNA Isopentenyltransferase MiaA
August 2010
Importance of extension for integrin
June 2010
Phytochrome
April 2010
Alg13 Subunit of N-Acetylglucosamine Transferase
February 2010
Hemolysin BL
January 2010
Secretagogin
December 2009
Two-component signaling
December 2009
Network coverage
November 2009
Pseudouridine Synthase TruA
November 2009
Unusual cell division
October 2009
Toxin-antitoxin VapBC-5
September 2009
Salicylic Acid Binding Protein 2
August 2009
Proofreading RNA
July 2009
Ykul structure solves bacterial signaling puzzle
July 2009
Hda and DNA Replication
June 2009
Controlling p53
May 2009
Mitotic checkpoint control
May 2009
Ribonuclease and Ribonuclease Inhibitor
April 2009
The elusive helicase
April 2009
Aquaglyceroporin
March 2009
High-energy storage system
February 2009
A new class of bacterial E3 ubiquitination enzymes
January 2009
Poly(A) RNA recognition
January 2009
Activating BAX
December 2008
Scavenger Decapping Enzyme DcpS
November 2008
Bacteriophage Lambda cII Protein
October 2008
New metal-binding domain
October 2008
Blocking AmtB
September 2008
T-Rex
September 2008
Aspartate Dehydrogenase
August 2008
RNase T
July 2008
Chronophin
May 2008

Research Themes Cell biology

Regulatory insights

SBKB [doi:10.1038/sbkb.2011.97]
Featured Article - September 2012
Short description: Structures of the JH2 pseudokinase domain provide clues to its role in normal and disease-associated JAK signaling.

Ribbon diagram of the JAK2 JH2. N lobe is light gray, C lobe is dark gray, αC is yellow and ATP is drawn in stick representation.

Human JAK2 tyrosine kinase associates with the cytoplasmic domain of cytokine receptors and is activated by receptor dimerization or rearrangement that is induced by cytokine binding. JAK2 activation is important for the initial innate immune response, as well as for myeloid cell development, proliferation and survival.

JAK2 is comprised of a FERM (band 4.1, ezrin, radixin, moesin) domain, important for association with cytokine receptors, an Src homology-2 (SH2) domain, a pseudokinase domain (JH2) and a C-terminal tyrosine kinase domain (JH1). JH2 is known to regulate the activity of JH1, but how it does so is unclear. Mutations to the JAK genes cause bone marrow diseases called myeloproliferative neoplasms (MPNs), and many of these mutations have been mapped to the JH2 region of JAK2 and result in constitutive JAK2 tyrosine kinase activity, suggesting an inhibitory function for JH2. However, some mutations in JH2 of JAK3 lead to loss of function, suggesting a positive regulatory role for this domain in JAK activity.

Recent work has shown that, surprisingly, JH2 is an active kinase domain that phosphorylates two sites on JH1 that negatively regulate its activity. To gain further insight into the activity of JH2, Silvennoinen, Hubbard and colleagues have determined the structures of wild type JAK2 JH2 (PDB 4FVP)and the V617F mutation (PDB 4FVR), the most commonly identified MPN mutation, in apo and Mg-ATP-bound forms.

The structures show that JH2 adopts the prototypical protein kinase fold. Similar to other kinases, Mg-ATP binds in the cleft formed between the N- and C-terminal lobes. However, the authors note a non-canonical mode of Mg-ATP binding that explains its lower rate of basal activity compared to JH1. Of greater interest is the effect the V617F mutation has on the structure of the JH2 domain. Val617 is located in a loop in the N lobe. While the V617F mutation does not affect nucleotide binding, it does result in rigidification of the N lobe αC helix that simulations suggest would facilitate activation of the JH1 domain.

While the structures don't fully delineate the mechanism by which JH2 regulates JAK signaling, they provide a starting point for further investigations. As the JH2 domain is a mutation hot spot, it may also provide an alternative target for small molecule therapeutics.

Michelle Montoya

References

  1. R.M. Bandaranayake et al. Crystal structures of the JAK2 pseudokinase domain and the pathogenic mutant of V617F.
    Nat Struct Mol Biol. 19, 754-759 (2012). doi:10.1038/nsmb.2348

Structural Biology Knowledgebase ISSN: 1758-1338
Funded by a grant from the National Institute of General Medical Sciences of the National Institutes of Health