Title : Structural basis for the growth factor activity of human
adenosine deaminase ADA2
Abstract :
- Two distinct adenosine deaminases, ADA1 and ADA2 , are found in humans
- ADA1 has an important role in lymphocyte function and inherited mutations in ADA1 result in severe combined immunodeficiency
- The recently isolated ADA2 belongs to the novel family of adenosine deaminase growth factors ( ADGFs ), which play an important role in tissue development
- The crystal structures of ADA2 and ADA2 bound to a transition state analogue presented here reveal the structural basis of the catalytic/signaling activity of ADGF / ADA2 proteins
- In addition to the catalytic domain , the structures discovered two ADGF / ADA2-specific domains of novel folds that mediate the protein dimerization and binding to the cell surface receptors
- This complex architecture is in sharp contrast with that of monomeric single domain ADA1
- An extensive glycosylation and the presence of a conserved disulfide bond and a signal peptide in ADA2 strongly suggest that ADA2 , in contrast to ADA1 , is specifically designed to act in the extracellular environment
- The comparison of catalytic sites of ADA2 and ADA1 demonstrates large differences in the arrangement of the substrate-binding pockets
- These structural differences explain the substrate and inhibitor specificity of adenosine deaminases and provide the basis for a rational design of ADA2-targeting drugs to modulate the immune system responses in pathophysiological conditions