Conserved asymmetry underpins homodimerization of Dicer-associated double-stranded RNA-binding proteins

Double-stranded RNA-binding domains (dsRBDs) are commonly found in modular proteins that interact with RNA. Two varieties of dsRBD exist: canonical Type A dsRBDs interact with dsRNA, while non-canonical Type B dsRBDs lack RNA-binding residues and instead interact with other proteins. In higher eukar...

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Bibliographic Details
Published in:Nucleic acids research 2017-12, Vol.45 (21), p.12577-12584
Main Authors: Heyam, Alex, Coupland, Claire E, Dégut, Clément, Haley, Ruth A, Baxter, Nicola J, Jakob, Leonhard, Aguiar, Pedro M, Meister, Gunter, Williamson, Michael P, Lagos, Dimitris, Plevin, Michael J
Format: Article
Language:English
Subjects:
Drosophila Proteins
Humans
Models, Molecular
Nuclear Magnetic Resonance, Biomolecular
Protein Domains
Protein Multimerization
RNA, Double-Stranded - metabolism
RNA-Binding Proteins - chemistry
RNA-Binding Proteins - metabolism
Structural Biology
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Summary:Double-stranded RNA-binding domains (dsRBDs) are commonly found in modular proteins that interact with RNA. Two varieties of dsRBD exist: canonical Type A dsRBDs interact with dsRNA, while non-canonical Type B dsRBDs lack RNA-binding residues and instead interact with other proteins. In higher eukaryotes, the microRNA biogenesis enzyme Dicer forms a 1:1 association with a dsRNA-binding protein (dsRBP). Human Dicer associates with HIV TAR RNA-binding protein (TRBP) or protein activator of PKR (PACT), while Drosophila Dicer-1 associates with Loquacious (Loqs). In each case, the interaction involves a region of the protein that contains a Type B dsRBD. All three dsRBPs are reported to homodimerize, with the Dicer-binding region implicated in self-association. We report that these dsRBD homodimers display structural asymmetry and that this unusual self-association mechanism is conserved from flies to humans. We show that the core dsRBD is sufficient for homodimerization and that mutation of a conserved leucine residue abolishes self-association. We attribute differences in the self-association properties of Loqs, TRBP and PACT to divergence of the composition of the homodimerization interface. Modifications that make TRBP more like PACT enhance self-association. These data are examined in the context of miRNA biogenesis and the protein/protein interaction properties of Type B dsRBDs.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkx928