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Nucleic Acids Res. 2016 Aug 19;44(14):6868-82. doi: 10.1093/nar/gkw575. Epub 2016 Jun 28.

SLIRP stabilizes LRPPRC via an RRM-PPR protein interface.

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Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, D-50931 Cologne, Germany
Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Proteomics Core Facility, Max Planck Institute for Biology of Ageing, D-50931 Cologne, Germany.
Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Nedlands, Western Australia 6009, Australia School of Chemistry and Biochemistry, The University of Western Australia, Crawley, Western Australia 6009, Australia.
Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, D-50931 Cologne, Germany Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden


LRPPRC is a protein that has attracted interest both for its role in post-transcriptional regulation of mitochondrial gene expression and more recently because numerous mutated variants have been characterized as causing severe infantile mitochondrial neurodegeneration. LRPPRC belongs to the pentatricopeptide repeat (PPR) protein family, originally defined by their RNA binding capacity, and forms a complex with SLIRP that harbours an RNA recognition motif (RRM) domain. We show here that LRPPRC displays a broad and strong RNA binding capacity in vitro in contrast to SLIRP that associates only weakly with RNA. The LRPPRC-SLIRP complex comprises a hetero-dimer via interactions by polar amino acids in the single RRM domain of SLIRP and three neighbouring PPR motifs in the second quarter of LRPPRC, which critically contribute to the LRPPRC-SLIRP binding interface to enhance its stability. Unexpectedly, specific amino acids at this interface are located within the PPRs of LRPPRC at positions predicted to interact with RNA and within the RNP1 motif of SLIRP's RRM domain. Our findings thus unexpectedly establish that despite the prediction that these residues in LRPPRC and SLIRP should bind RNA, they are instead used to facilitate protein-protein interactions, enabling the formation of a stable complex between these two proteins.

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