Cleavage kinetics of human mitochondrial RNase P and contribution of its non-nuclease subunits

Author:

Vilardo Elisa1ORCID,Toth Ursula1,Hazisllari Enxhi1,Hartmann Roland K2,Rossmanith Walter1ORCID

Affiliation:

1. Center for Anatomy & Cell Biology, Medical University of Vienna , 1090 Vienna , Austria

2. Institute of Pharmaceutical Chemistry, Philipps-University Marburg , 35037  Marburg , Germany

Abstract

Abstract RNase P is the endonuclease responsible for the 5′ processing of precursor tRNAs (pre-tRNAs). Unlike the single-subunit protein-only RNase P (PRORP) found in plants or protists, human mitochondrial RNase P is a multi-enzyme assembly that in addition to the homologous PRORP subunit comprises a methyltransferase (TRMT10C) and a dehydrogenase (SDR5C1) subunit; these proteins, but not their enzymatic activities, are required for efficient pre-tRNA cleavage. Here we report a kinetic analysis of the cleavage reaction by human PRORP and its interplay with TRMT10C-SDR5C1 including 12 different mitochondrial pre-tRNAs. Surprisingly, we found that PRORP alone binds pre-tRNAs with nanomolar affinity and can even cleave some of them at reduced efficiency without the other subunits. Thus, the ancient binding mode, involving the tRNA elbow and PRORP’s PPR domain, appears basically retained by human PRORP, and its metallonuclease domain is in principle correctly folded and functional. Our findings support a model according to which the main function of TRMT10C-SDR5C1 is to direct PRORP’s nuclease domain to the cleavage site, thereby increasing the rate and accuracy of cleavage. This functional dependence of human PRORP on an extra tRNA-binding protein complex likely reflects an evolutionary adaptation to the erosion of canonical structural features in mitochondrial tRNAs.

Funder

Austrian Science Fund

Vienna Science and Technology Fund

German Research Foundation

Publisher

Oxford University Press (OUP)

Subject

Genetics

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