A Histidine Kinase as a Target for Autoimmune Diseases

Share

NDPK-B crystal structure

Crystal structure of the hexameric NDPK-B protein - PDB ID=3BBB

The nucleoside diphosphate kinases (NDPK) comprise a family of 10 members encoded by the Nme (non-metatstatic cell) gene family. These kinases are capable of transferring the γ-phosphate of nucleoside triphosphates to nucleoside diphosphates, which is accomplished via a phospho-histidine intermediate. Since their discovery, the NDPKs have been shown to play a role in numerous cellular processes. Of the 10 members, NDPK-A and B (also known as NM23-H1 and NM23-H2 respectively) are ubiquitously expressed and account for >95% of NDPK activity in most cells.

NDPK-A and B regulate cellular processes through a variety of mechanisms including generation of nucleoside triphosphates, histidine phosphorylation, protein-protein interactions and regulation of downstream signalling pathways. Interestingly, the NDPKs are currently the only known histidine kinases found in mammals.

Despite sharing 88% sequence identity, NDPK-A and B have each been associated with specific functions. Nevertheless, there appears to be significant redundancy within the family. NDPK-A knockout mice have been reported to be phenotypically normal, with the exception of reduced birth weight and delayed mammary development. However, double knockout of NDPK-A and B results in stunted mice that die perinatally as a result of severe anaemia and abnormal erythroid development.

Now a team at New York University Medical Center have reported the mouse knockout of NDPK-B. Previously the team had shown that NDPK-B activates the K+ channel, KCa3.1, by phosphorylation of 358His in the KCa3.1 carboxy terminus. Since this activation is required for T-cell receptor stimulation of Ca2+ flux and proliferation of naïve human CD4+ T-cells, the team speculated that inhibition of NDPK-B could represent a target for therapy of autoimmune diseases.

The NDPK-B knockout mice were phenotypically normal at birth, with normal T and B cell development. KCa3.1 channel activity and cytokine production were defective in Th1 and Th2 cells (but normal in Th17 cells), however, confirming the importance of NDPK-B in T cell activation. The data support the concept of NDPK-B inhibition as a therapeutic strategy, although specificity for NDPK-B over the A isoform will be necessary. Given the degree of sequence conservation between the two isoforms, this could be a significant challenge.


Leave a Reply

Your email address will not be published. Required fields are marked *

*