Journal of Biological Chemistry
Volume 285, Issue 16, 16 April 2010, Pages 12367-12377
Journal home page for Journal of Biological Chemistry

Protein Structure and Folding
Structural Basis for the Growth Factor Activity of Human Adenosine Deaminase ADA2*

https://doi.org/10.1074/jbc.M109.083527Get rights and content
Under a Creative Commons license
open access

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.

Diseases/Cancer/Leukemia
Enzymes/Catalysis
Hormones/Growth Factors
Nucleoside
Protein/Ligand Binding
Protein/Structure
Protein/Zinc
Adenosine Deaminase

Cited by (0)

The atomic coordinates and structure factors (codes 3LGD and 3LGG) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

*

This work was supported by grants from the Swedish Research Council (K2008-58X-20689-01-3) and FORMAS (221-2007-1057) (to Ant. V. Z.), European Molecular Biology Organization Grant ALT-978-2005 and Human Frontier of Science Program (HFSP) Long Term Fellowship LT00395-2006-L (to And. V. Z.), and grants from INSERM (Avenir) and HFSP carrier development award (CDA0040-2005C) (to G. L.).

This article was selected as a Paper of the Week.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1S–2S and supplemental Figs. 1S–4S.