PSI Structural Biology Knowledgebase

PSI | Structural Biology Knowledgebase
Header Icons
E-Collection

Related Articles
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: Bespoke Design of Repeat Proteins
June 2015
Design and Evolution: Tunable Antibody Binders
June 2015
Immunity: Clustering Immunoglobulins
June 2014
Immunity: Conformational Capture
June 2014
Immunity: One Antibody to Rule Them All
June 2014
Immunity: Tissue Contribution
June 2014
Caught in the Act
December 2013
Serum Albumins and Allergies
October 2013
The Immune System: A Brotherhood of Immunoglobulins
June 2013
The Immune System: A Strong Competitor
June 2013
The Immune System: Strand Swapping for T-Cell Inhibition
June 2013
The Immune System: Super Cytokines
June 2013
Tuning Immune Response with Costimulation
June 2013
Regulatory insights
September 2012
Serum albumin diversity
August 2012
Substrate specificity sleuths
April 2012
Buena VISTA
February 2012
Analyzing an allergen
January 2012
TLR4 regulation: heads or tails?
October 2011
Binding complement with complementarity
June 2011

Research Themes Immunology

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