Structure of the dimerization domain of DiGeorge critical region 8.
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.
Senturia
Rachel
R
Department of Biological Chemistry in David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA.
Faller
Michael
M
Yin
Sheng
S
Loo
Joseph A
JA
Cascio
Duilio
D
Sawaya
Michael R
MR
Hwang
Daniel
D
Clubb
Robert T
RT
Guo
Feng
F
D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins; D021241:Spectrometry, Mass, Electrospray Ionization
C474043:DGCR8 protein, human; D011506:Proteins; D016601:RNA-Binding Proteins