期刊
PROTEIN SCIENCE
卷 19, 期 7, 页码 1354-1365出版社
WILEY
DOI: 10.1002/pro.414
关键词
dimerization; WW motif; X-ray crystallography; 3D domain swapping; heme; RNA-binding protein; microRNA processing
资金
- Jonsson Comprehensive Cancer Center at UCLA
- March of Dimes Foundation [5-FY06-592]
- NIH [GM080563, RR20004, AI52217]
- DOE [DE-FC02-02ER63421, DE-AC02-06CH11357]
- NCRR [RR-15301]
Maturation of microRNAs (miRNAs, similar to 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 angstrom 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.
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