Prediction of the structure of human Janus kinase 2 (JAK2) comprising the two carboxy-terminal domains reveals a mechanism for autoregulation

The structure of human Janus kinase 2 (JAK2) comprising the two C-terminal domains (JH1 and JH2) was predicted by application of homology modelling te chniques. JH1 and JH2 represent the tyrosine kinase and tyrosine kinase-lik e domains, respectively, and are crucial for function and regulation of the protein. A comparison between the structures of the two domains is made an d structural differences are highlighted. Prediction of the relative orient ation of JH1 and JH2 was aided by a newly developed method for the detectio n of correlated amino acid mutations. Analysis of the interactions between the two domains led to a model for the regulatory effect of JH2 on JH1, The predictions are consistent with available experimental data on JAK2 or rel ated proteins and provide an explanation for inhibition of JH1 tyrosine kin ase activity by the adjacent JH2 domain.