Structure of the dimerization domain of DiGeorge critical region 8.
Publication Type:Journal Article
Source:Protein Sci, Volume 19, Issue 7, p.1354-65 (2010)
Keywords:Amino Acid Sequence, Crystallography, X-Ray, Humans, Models, Molecular, Molecular Sequence Data, Protein Multimerization, Protein Structure, Secondary, Protein Structure, Tertiary, Proteins, RNA-Binding Proteins, Spectrometry, Mass, Electrospray Ionization
<p>Maturation of microRNAs (miRNAs, approximately 22nt) from long primary transcripts [primary miRNAs (pri-miRNAs)] is regulated during development and is altered in diseases such as cancer. The first processing step is a cleavage mediated by the Microprocessor complex containing the Drosha nuclease and the RNA-binding protein DiGeorge critical region 8 (DGCR8). We previously reported that dimeric DGCR8 binds heme and that the heme-bound DGCR8 is more active than the heme-free form. Here, we identified a conserved dimerization domain in DGCR8. Our crystal structure of this domain (residues 298-352) at 1.7 A resolution demonstrates a previously unknown use of a WW motif as a platform for extensive dimerization interactions. The dimerization domain of DGCR8 is embedded in an independently folded heme-binding domain and directly contributes to association with heme. Heme-binding-deficient DGCR8 mutants have reduced pri-miRNA processing activity in vitro. Our study provides structural and biochemical bases for understanding how dimerization and heme binding of DGCR8 may contribute to regulation of miRNA biogenesis.</p>