Structural basis for the growth factor activity of human adenosine deaminase ADA2

Anton V. Zavialov, Xiaodi Yu, Dorothe Spillmann, Gregoire Lauvau, Andrey V. Zavialo

Research output: Contribution to journalArticle

47 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)12367-12377
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number16
DOIs
StatePublished - Apr 16 2010

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Adenosine Deaminase
Intercellular Signaling Peptides and Proteins
Catalytic Domain
Adenosine Deaminase Inhibitors
Protein Multimerization
Severe Combined Immunodeficiency
Cell Surface Receptors
Glycosylation
Drug Delivery Systems
Protein Sorting Signals
Substrate Specificity
Protein Binding
Disulfides
Lymphocytes
Dimerization
Immune system
Immune System
Substrates
Proteins
Mutation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Structural basis for the growth factor activity of human adenosine deaminase ADA2. / Zavialov, Anton V.; Yu, Xiaodi; Spillmann, Dorothe; Lauvau, Gregoire; Zavialo, Andrey V.

In: Journal of Biological Chemistry, Vol. 285, No. 16, 16.04.2010, p. 12367-12377.

Research output: Contribution to journalArticle

Zavialov, Anton V. ; Yu, Xiaodi ; Spillmann, Dorothe ; Lauvau, Gregoire ; Zavialo, Andrey V. / Structural basis for the growth factor activity of human adenosine deaminase ADA2. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 16. pp. 12367-12377.
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