Structure of mitochondrial poly(A) RNA polymerase reveals the structural basis for dimerization, ATP selectivity and the SPAX4 disease phenotype

Mikalai Lapkouski; B Martin Hällberg

doi:10.1093/nar/gkv861

Structure of mitochondrial poly(A) RNA polymerase reveals the structural basis for dimerization, ATP selectivity and the SPAX4 disease phenotype

Nucleic Acids Res. 2015 Oct 15;43(18):9065-75. doi: 10.1093/nar/gkv861. Epub 2015 Aug 28.

Authors

Mikalai Lapkouski¹, B Martin Hällberg²

Affiliations

¹ Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden Röntgen-Ångström-Cluster, Karolinska Institutet Outstation, Centre for Structural Systems Biology, DESY-Campus, 22607 Hamburg, Germany.
² Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden Röntgen-Ångström-Cluster, Karolinska Institutet Outstation, Centre for Structural Systems Biology, DESY-Campus, 22607 Hamburg, Germany European Molecular Biology Laboratory, Hamburg Unit, 22607 Hamburg, Germany Martin.Hallberg@ki.se.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / analogs & derivatives
Adenosine Triphosphate / chemistry
Animals
Binding Sites
Chickens
DNA-Directed RNA Polymerases / chemistry*
DNA-Directed RNA Polymerases / genetics
DNA-Directed RNA Polymerases / metabolism
Dimerization
Humans
Intellectual Disability / genetics
Mitochondrial Proteins / chemistry*
Mitochondrial Proteins / genetics
Mitochondrial Proteins / metabolism
Models, Molecular
Muscle Spasticity / genetics
Mutation
Nucleotides / chemistry
Nucleotides / metabolism
Nucleotidyltransferases / chemistry
Optic Atrophy / genetics
Phenotype
RNA / metabolism
Schizosaccharomyces pombe Proteins / chemistry
Spinocerebellar Ataxias / genetics

Substances

Mitochondrial Proteins
Nucleotides
Schizosaccharomyces pombe Proteins
adenosine 5'-O-(3-thiotriphosphate)
RNA
Adenosine Triphosphate
Nucleotidyltransferases
Cid1 protein, S pombe
DNA-Directed RNA Polymerases
MTPAP protein, human

Supplementary concepts

Spastic Ataxia

Associated data

PDB/5A2V
PDB/5A2W
PDB/5A2X
PDB/5A2Y
PDB/5A2Z