Abstract
Polyadenylation, performed by poly(A) polymerases (PAPs), is a ubiquitous post-transcriptional modification that plays key roles in multiple aspects of RNA metabolism. Although cytoplasmic and nuclear PAPs have been studied extensively, the mechanism by which mitochondrial PAP (mtPAP) selects adenosine triphosphate over other nucleotides is unknown. Furthermore, mtPAP is unique because it acts as a dimer. However, mtPAP's dimerization requirement remains enigmatic. Here, we show the structural basis for mtPAP's nucleotide selectivity, dimerization and catalysis. Our structures reveal an intricate dimerization interface that features an RNA-recognition module formed through strand complementation. Further, we propose the structural basis for the N478D mutation that drastically reduces the length of poly(A) tails on mitochondrial mRNAs in patients with spastic ataxia 4 (SPAX4), a severe and progressive neurodegenerative disease.
Highlights
Polyadenylation is a ubiquitous mRNA post-translational modification that was first discovered in eukaryotic cells in 1960 [1]
The purified mitochondrial PAP (mtPAP) crystallized as a dimer as observed in solution (Supplementary Figure S1B). mtPAP consisted of an N-terminal domain (NTD: 52–194 aa) and of palm (195– 341 aa) and fingers (342–527 aa) domains (Figure 1A–C)
A charged path is formed upon dimerization and we propose that the mRNA may follow this path (Figure 6A–C)
Summary
Polyadenylation is a ubiquitous mRNA post-translational modification that was first discovered in eukaryotic cells in 1960 [1]. Most attention has been devoted to the polyadenylation that occurs in the cytosol and the nucleus, and our understanding of polyadenylation in mitochondria is, rudimentary. Mammalian mitochondrial transcription results in two large polycistronic precursors, which are processed by the RNA-processing machinery into individual tRNAs, rRNAs and mRNAs. All but one of the mRNAs are further matured by the addition of a polyadenine tail [2,3,4]. Polyadenylation alters the fate of mRNAs in several ways. It can increase mRNA stability, stimulate translation initiation, promote degradation or be required for completing certain stop codons that are not encoded in mtDNA [4,5,6]
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