tRNase Z reaction is central to tRNA maturation

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DESCRIPTION (provided by applicant): Transfer RNA (tRNA) is central to protein synthesis. Like other RNAs, tRNA is transcribed as a precursor and must undergo maturation. RNase P removes the 5' leader. The endonuclease tRNase Z removes the 3' trailer so that CCA can be added by tRNA nucleotidyltransferase. tRNase Z reaction is thus a critical step in pre- tRNA maturation. A flexible arm (FA) is extruded from the body of tRNase Z remote from the active site. The globular FA hand principally binds to the elbow (D/T loops) of tRNA, far from the scissile bond. Naturally occurring mutations in human mitochondrial tRNAs are associated with maternally transmitted diseases and syndromes, principally myopathies. [Aim 1] Does the distribution of pathogenesis-related mitochondrial tRNA mutations correlate with tRNA structure changes and effects on tRNase Z processing? Effects of pathogenesis-related T loop substitutions will be investigated. [Aim 2] Does protease susceptibility report on flexibility of the tRNase Z FA? The mass spectroscopic analysis will shed light on a novel mechanism of substrate recognition. [Aim 3] Might pre-tRNA 3' trailers enter a regulatory network following tRNase Z reaction? We will investigate binding of the pre-tRNA 3' trailer products of tRNase Z cleavage to La and members of the Ago family in early steps of the hypothesized pathway.