Molecular mechanisms of ADAR2 localization and substrate specificity

Abstract

ADAR2-mediated adenosine-to-inosine (A-to-I) RNA editing can affect the coding potential, splicing pattern, stability, and localization of the targeted RNA transcripts. ADAR2 contains two double-stranded RNA binding motifs (dsRBM) and a conserved adenosine deaminase domain. To investigate how the dsRBMs of ADAR2 bind to natural substrates, we developed an NMR-based model of the complex formed between the two dsRBMs and an RNA duplex derived from a naturally-occurring ADAR2 substrate. These structural studies demonstrated that dsRBMs recognize specific structural determinants and hence contribute to substrate specificity. In addition, we demonstrated that the dsRBMs of ADAR2 differ in their ability to modulate subnuclear localization and editing activity although their sequences/structures are highly conserved, emphasizing the functional inequality between members of this conserved protein motif family.