Structural basis of dimerization and nucleic acid binding of human DBHS proteins NONO and PSPC1

Abstract The Drosophila behaviour/human splicing (DBHS) proteins are a family of RNA/DNA binding cofactors liable for a range of cellular processes. DBHS proteins include the non-POU domain-containing octamer-binding protein (NONO) and paraspeckle protein component 1 (PSPC1), proteins capable of for...

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Published in:Nucleic acids research 2022-01, Vol.50 (1), p.522-535
Main Authors: Knott, Gavin J, Chong, Yee Seng, Passon, Daniel M, Liang, Xue-hai, Deplazes, Evelyne, Conte, Maria R, Marshall, Andrew C, Lee, Mihwa, Fox, Archa H, Bond, Charles S
Format: Article
Language:English
Subjects:
Dimerization
DNA-Binding Proteins - metabolism
Humans
Models, Molecular
Protein Conformation
RNA - metabolism
RNA Splicing
RNA-Binding Proteins - metabolism
Structural Biology
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Summary:Abstract The Drosophila behaviour/human splicing (DBHS) proteins are a family of RNA/DNA binding cofactors liable for a range of cellular processes. DBHS proteins include the non-POU domain-containing octamer-binding protein (NONO) and paraspeckle protein component 1 (PSPC1), proteins capable of forming combinatorial dimers. Here, we describe the crystal structures of the human NONO and PSPC1 homodimers, representing uncharacterized DBHS dimerization states. The structures reveal a set of conserved contacts and structural plasticity within the dimerization interface that provide a rationale for dimer selectivity between DBHS paralogues. In addition, solution X-ray scattering and accompanying biochemical experiments describe a mechanism of cooperative RNA recognition by the NONO homodimer. Nucleic acid binding is reliant on RRM1, and appears to be affected by the orientation of RRM1, influenced by a newly identified ‘β-clasp’ structure. Our structures shed light on the molecular determinants for DBHS homo- and heterodimerization and provide a basis for understanding how DBHS proteins cooperatively recognize a broad spectrum of RNA targets. Graphical Abstract Graphical Abstract Binding of nucleic acids by DBHS protein dimers involves RRM1 and RRM2 of each monomer. Although the two identical binding sites in a homodimer are not linked, independent rearrangement of RRM1 domains to accommodate nucleic acid requires the unfastening of the N-terminal β-clasp.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkab1216