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 techniques. JH1 and JH2 represent the tyrosine kinase and tyrosine kinase-like domains, respectively, and are crucial for function and regulation of the protein. A comparison between the structures of the two domains is made and structural differences are highlighted. Prediction of the relative orientation of JH1 and JH2 was aided by a newly developed method for the detection 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 related proteins and provide an explanation for inhibition of JH1 tyrosine kinase activity by the adjacent JH2 domain.
Lindauer
K
K
Department of Chemistry, Queen Mary and Westfield College, University of London, Mile End Road, London E1 4NS, UK.
Loerting
T
T
Liedl
K R
KR
Kroemer
R T
RT
D000595:Amino Acid Sequence; D016384:Consensus Sequence; D017124:Conserved Sequence; D003627:Data Interpretation, Statistical; D004789:Enzyme Activation; D006706:Homeostasis; D006801:Humans; D007133:Immunoglobulin Joining Region / Q000737:chemistry; D053614:Janus Kinase 2; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011494:Protein Kinases / Q000737:chemistry; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry*; D011518:Proto-Oncogene Proteins; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D007133:Immunoglobulin Joining Region; D011518:Proto-Oncogene Proteins; D011494:Protein Kinases; C060137:carboxy-terminal domain kinase; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2