title: Structure of the dimerization domain of DiGeorge critical region 8.
abstract: 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.
authors.affiliation: Department of Biological Chemistry in David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Senturia
authors.forename: Michael
authors.initials: M
authors.lastname: Faller
authors.forename: Sheng
authors.initials: S
authors.lastname: Yin
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Loo
authors.forename: Duilio
authors.initials: D
authors.lastname: Cascio
authors.forename: Michael R
authors.initials: MR
authors.lastname: Sawaya
authors.forename: Daniel
authors.initials: D
authors.lastname: Hwang
authors.forename: Robert T
authors.initials: RT
authors.lastname: Clubb
authors.forename: Feng
authors.initials: F
authors.lastname: Guo
mesh_terms: 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
chemical_list: C474043:DGCR8 protein, human; D011506:Proteins; D016601:RNA-Binding Proteins