PSI Structural Biology Knowledgebase

PSI | Structural Biology Knowledgebase
Header Icons
E-Collection

Related Articles
Design and Evolution: Molecular Sleuthing Reveals Drug Selectivity
June 2015
Families in Gene Neighborhoods
June 2015
Ryanodine Receptor
April 2015
CCR5 and HIV Infection
January 2015
Drug Targets: Bile Acids in Motion
September 2014
Drug Targets: S1R's Ligands and Partners
September 2014
P2Y Receptors and Blood Clotting
September 2014
Bacterial CDI Toxins
June 2014
Glucagon Receptor
April 2014
Viroporins
March 2014
Microbial Pathogenesis: Targeting Drug Resistance in Mycobacterium tuberculosis
February 2014
Design and Discovery: Virtual Drug Screening
January 2014
Cancer Networks: IFI16-mediated p53 Activation
November 2013
G Proteins and Cancer
November 2013
Drug Discovery: Antidepressant Potential of 6-NQ SERT Inhibitors
October 2013
Drug Discovery: Finding Druggable Targets
October 2013
Drug Discovery: Identifying Dynamic Networks by CONTACT
October 2013
Drug Discovery: Modeling NET Interactions
October 2013
Membrane Proteome: GPCR Substrate Recognition and Functional Selectivity
August 2013
Infectious Diseases: Determining the Essential Structome
May 2013
NDM-1 and Antibiotics
May 2013
Microbial Pathogenesis: Computational Epitope Prediction
January 2013
Microbial Pathogenesis: Influenza Inhibitor Screen
January 2013
Microbial Pathogenesis: Measles Virus Attachment
January 2013
Cytochrome Oxidase
November 2012
Membrane Proteome: The ABCs of Transport
November 2012
Bacterial Phosphotransferase System
October 2012
Regulatory insights
September 2012
Solute Channels
September 2012
Pocket changes
July 2012
Receptor bias
July 2012
Anthrax Stealth Siderophores
June 2012
G Protein-Coupled Receptors
May 2012
Substrate specificity sleuths
April 2012
Reading out regioselectivity
December 2011
Superbugs and Antibiotic Resistance
December 2011
Terminal activation
December 2011
A change to resistance
November 2011
Docking and rolling
October 2011
Breaking down the defenses
September 2011
A2A Adenosine Receptor
May 2011
Cell wall recycler
May 2011
Subtly different
March 2011
CXCR4
January 2011
Subtle shifts
January 2011
ABA receptor diversity
November 2010
COX inhibition: Naproxen by proxy
November 2010
Zinc Transporter ZntB
July 2010
Peptidoglycan binding: Calcium-free killing
June 2010
Treating sleeping sickness
May 2010
Bacterial spore kinase
April 2010
Antibiotics and Ribosome Function
March 2010
Safer Alzheimer's drugs?
March 2010
Anthrax evasion tactics
September 2009
GPCR subunits: Separate but not equal
September 2009
Antibiotic target
August 2009
Salicylic Acid Binding Protein 2
August 2009
Lysostaphin
July 2009
Tackling influenza
June 2009
Bacterial Leucine Transporter, LeuT
May 2009
Anthrax stealth molecule
March 2009
Drug targets to aim for
February 2009
High-energy storage system
February 2009
Transporter mechanism in sight
February 2009
Scavenger Decapping Enzyme DcpS
November 2008
Blocking AmtB
September 2008

Research Themes Drug discovery

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