Structure–function relationships in the Nab2 polyadenosine‐RNA binding Zn finger protein family

Abstract

The poly(A) RNA binding Zn finger ribonucleoprotein Nab2 functions to control the length of 3′ poly(A) tails in Saccharomyces cerevisiae as well as contributing to the integration of the nuclear export of mature mRNA with preceding steps in the nuclear phase of the gene expression pathway. Nab2 is constructed from an N‐terminal PWI‐fold domain, followed by QQQP and RGG motifs and then seven CCCH Zn fingers. The nuclear pore‐associated proteins Gfd1 and Mlp1 bind to opposite sides of the Nab2 N‐terminal domain and function in the nuclear export of mRNA, whereas the Zn fingers, especially fingers 5–7, bind to A‐rich regions of mature transcripts and function to regulate poly(A) tail length as well as mRNA compaction prior to nuclear export. Nab2 Zn fingers 5–7 have a defined spatial arrangement, with fingers 5 and 7 arranged on one side of the cluster and finger 6 on the other side. This spatial arrangement facilitates the dimerization of Nab2 when bound to adenine‐rich RNAs and regulates both the termination of 3′ polyadenylation and transcript compaction. Nab2 also functions to coordinate steps in the nuclear phase of the gene expression pathway, such as splicing and polyadenylation, with the generation of mature mRNA and its nuclear export. Nab2 orthologues in higher Eukaryotes have similar domain structures and play roles associated with the regulation of splicing and polyadenylation. Importantly, mutations in the gene encoding the human Nab2 orthologue ZC3H14 and cause intellectual disability.

The Polyadenosine RNA Binding Protein ZC3H14 is Required in Mice for Proper Dendritic Spine Density

“…3A,C) generated by alternative splicing (Leung et al, 2009). Both ZC3H14 Isoform 1 (Iso 1) and Isoform 3 (Iso 3) include the functionally important domains of ZC3H14, namely the zinc finger RNA binding domain (Fasken, Corbett, & Stewart, 2019; S. M. Kelly et al, 2010) and the N-terminal PWI-like domain (Fasken et al, 2019; Grant et al, 2008), as well as a predicted nuclear localization signal (Fig.…”

Altered rRNA processing disrupts nuclear RNA homeostasis via competition for the poly(A)-binding protein Nab2

“…Current structure-function and RNA-binding data indicate that Nab2 has a strong preference for polyadenine sequences ( 42 , 101 ), indicating that Nab2 recruitment to polyadenylated pre-rRNAs could initiate enp1-1 phenotypes. However, Nab2 association with non-polyadenine sequences in the middle of mRNA transcripts has also been demonstrated ( 42 , 102 ), raising the possibility that Nab2 may as well bind other regions of pre-rRNAs and other RNAs.…”

The Nab2 RNA binding protein promotes sex-specific splicing ofSex lethalinDrosophilaneuronal tissue

“…ZC3H14 is broadly expressed in many tissues and cell types but mutations in the human ZC3H14 gene are associated with a heritable form of intellectual disability (Pak et al, 2011), implying an important requirement for this protein in the central nervous system. ZC3H14 has well-conserved homologs in eukaryotes, including S. cerevisiae Nuclear poly(A)-binding protein 2 (Nab2), Drosophila melanogaster Nab2, C. elegans SUT-2 and murine ZC3H14 (Fasken et al, 2019). Zygotic loss of ZC3H14 in mice and Drosophila impairs neuronal function (Pak et al, 2011; Rha et al, 2017), while neuron-specific depletion of Drosophila Nab2 is sufficient to replicate these effects (Pak et al, 2011).…”