Erlacher Lab – Research
Protein synthesis is a central process in all living organisms. The key components of this process are ribosomes—multifunctional ribonucleoprotein (RNP) complexes that serve as the cellular machinery for protein synthesis. They translate genetic information from messenger RNA (mRNA) into proteins through a highly coordinated process involving numerous molecular components. RNA plays an essential role in translation, with all RNA types involved being modified to varying degrees. Our research aims to contribute to a better understanding of the molecular interactions of RNA during translation and how modifications modulate translation efficiency and accuracy.
tRNA modifications and their role in superwobbling tRNAs
During translation, 61 different codons must be translated into sequences of 20(21) amino acids, a process in which tRNAs act as essential adapters, transforming the 4-letter genetic code into amino acid sequences. Interestingly, the number tRNAs required to decode the almost universal genetic code varies greatly between organisms. While certain eukaryotes require up to 55 different tRNAs, some bacteria depend on as few as 28.
In this project, we strive to better understand how organisms can maintain efficient protein synthesis with reduced numbers of tRNAs, and which features of the tRNAs are required to enable an extended decoding capability. Our goal is to reveal the extent to which tRNA modifications and sequence variations contribute to different decoding capabilities and compensate for limited tRNA diversity.
Figure: Secondary structure of the standard E. coli tRNAValUAC and the superwobbling M. capricolum tRNAValUAC.
Genetic code expansion
Although the natural genetic code—utilizing 4 nucleotides to encode 20 (or 21) standard amino acids—enables the generation of a vast array of functional proteins and peptides, the expansion of the genetic code has long been pursued to introduce new chemical functionalities. Through the systematic introduction of modified nucleotides into both mRNA codons and tRNA anticodons, we aim to establish unique base-pairing partners that facilitate position-specific incorporation of non-natural amino acids. This approach will provide an alternative strategy for producing peptides and proteins carrying specific non-natural amino acids with unprecedented specificity.
mRNA modifications
In recent years, mRNA modifications have gained significant attention as they have been shown to modulate gene expression at multiple levels. While the regulatory function of these RNA modifications is well-established, the extent to which specific modifications contribute to particular cellular processes remains largely unknown. By systematically introducing different modifications into the untranslated regions (UTRs) and coding sequences (CDS) of eukaryotic mRNAs, we gain detailed insights into the roles of various modifications, with primary focus on protein synthesis and RNA stability. In addition, we study to what extent the impact of mRNA modifications differs from cell type to cell type.