Abstract
Human hnRNP A2/B1 is an RNA-binding protein that plays important roles in many biological processes, including maturation, transport, and metabolism of mRNA, and gene regulation of long noncoding RNAs. hnRNP A2/B1 was reported to control the microRNAs sorting to exosomes and promote primary microRNA processing as a potential m6A “reader.” hnRNP A2/B1 contains two RNA recognition motifs that provide sequence-specific recognition of RNA substrates. Here, we determine crystal structures of tandem RRM domains of hnRNP A2/B1 in complex with various RNA substrates, elucidating specific recognitions of AGG and UAG motifs by RRM1 and RRM2 domains, respectively. Further structural and biochemical results demonstrate multivariant binding modes for sequence-diversified RNA substrates, supporting a RNA matchmaker mechanism in hnRNP A2/B1 function. Moreover, our studies in combination with bioinformatic analysis suggest that hnRNP A2/B1 may mediate effects of m6A through a “m6A switch” mechanism, instead of acting as a direct “reader” of m6A modification.
Highlights
Human Heterogeneous nuclear ribonucleoproteins (hnRNPs) A2/B1 is an RNA-binding protein that plays important roles in many biological processes, including maturation, transport, and metabolism of mRNA, and gene regulation of long noncoding RNAs. hnRNP A2/B1 was reported to control the microRNAs sorting to exosomes and promote primary microRNA processing as a potential m6A “reader.” hnRNP A2/B1 contains two RNA recognition motifs that provide sequence-specific recognition of RNA substrates
This suggested that the construct containing the tandem RNA recognition motif (RRM) of hnRNP A2/B1 is sufficient for binding target RNAs
The RNA-binding domain of hnRNP A2/B1 comprises two RNA recognition motifs, RRM1 and RRM2, which is followed by a Cterminal glycine-rich region. hnRNP A2/B1 was previously demonstrated to bind UUAGGG and UAG RNA motifs through various analyses[37, 38]
Summary
Human hnRNP A2/B1 is an RNA-binding protein that plays important roles in many biological processes, including maturation, transport, and metabolism of mRNA, and gene regulation of long noncoding RNAs. hnRNP A2/B1 was reported to control the microRNAs sorting to exosomes and promote primary microRNA processing as a potential m6A “reader.” hnRNP A2/B1 contains two RNA recognition motifs that provide sequence-specific recognition of RNA substrates. The B1 isoform contains an insertion of 12 amino acids (aa) at its N terminus[7, 8] Both isoforms have an RNAbinding domain (RBD) composed of tandem RRMs separated by a 15-aa linker, and a C-terminal Gly-rich low complexity (LC) region that includes a prion-like domain (PrLD), an RGG box, and a PY-motif containing a M9 nuclear localization signal (PYNLS)[9,10,11]. These domains are represented schematically with residue numbers based on the hnRNP B1 isoform (Fig. 1a). HnRNP A2/B1 is linked to several biological processes and diseases, especially neurodegenerative disorders, e.g., mutations in core PrLD in hnRNP A2/B1 cause multisystem proteinopathy and amyotrophic lateral sclerosis (ALS), through promoting excess incorporation of hnRNP A2/B1 into stress granules and driving the formation of cytoplasmic inclusions in animal models9. hnRNP A2/B1 regulates hESC self-renewal and pluripotency[12]
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