Poster abstracts
Poster number 14 submitted by Nathan Howell
Determinants of substrate specificity for the Trm10 family of tRNA modification enzymes
Nathan Howell (OSBP), Aiswarya Krishnamohan (OSBP), Jane Jackman (OSBP)
Abstract:
Substantial biological resources are invested into producing functional tRNA molecules, including an extensive system of post-transcriptional nucleotide modifications. In this universal process, chemical functional groups are changed, rearranged, and added to individual nucleotides in a specific pattern for each target tRNA. One such modification is the addition of a methyl group to the N-1 atom of ninth-position purines (m1N9), which occurs in archaea and eukarya and is catalyzed by the Trm10 family of enzymes. Here we explain an apparent lack of functional redundancy in separate, cytosolic Trm10 homologs in humans (TRMT10A and TRMT10B) by demonstrating that they have distinct substrate specificities, consistent with known modification patterns in human tRNA, genetic work in yeast, and disease states in humans. Additionally, diverse experiments suggest an induced-fit mechanism of substrate recognition for the Trm10 family, in which tRNA molecules are selected based on correct tertiary structure and dynamics, particularly in the core region, which results in an ability to undergo correct conformational changes and form a catalytically-productive complex. In particular, the structure probed by Trm10 appears to be sensitive to other modifications of tRNA core nucleotides, suggesting a mechanism for interdependence and potential regulation. These results increase our understanding of the important biology of eukaryotic tRNA modification systems, which can aid in future treatment of the diseases in which their aberrant function is increasingly implicated.
Keywords: tRNA modifications, enzymology, Trm10