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Human tRNAs with inosine 34 are essential to efficiently translate eukarya-specific low-complexity proteins.

ABSTRACT: The modification of adenosine to inosine at the wobble position (I34) of tRNA anticodons is an abundant and essential feature of eukaryotic tRNAs. The expansion of inosine-containing tRNAs in eukaryotes followed the transformation of the homodimeric bacterial enzyme TadA, which generates I34 in tRNAArg and tRNALeu, into the heterodimeric eukaryotic enzyme ADAT, which modifies up to eight different tRNAs. The emergence of ADAT and its larger set of substrates, strongly influenced the tRNA composition and codon usage of eukaryotic genomes. However, the selective advantages that drove the expansion of I34-tRNAs remain unknown. Here we investigate the functional relevance of I34-tRNAs in human cells and show that a full complement of these tRNAs is necessary for the translation of low-complexity protein domains enriched in amino acids cognate for I34-tRNAs. The coding sequences for these domains require codons translated by I34-tRNAs, in detriment of synonymous codons that use other tRNAs. I34-tRNA-dependent low-complexity proteins are enriched in functional categories related to cell adhesion, and depletion in I34-tRNAs leads to cellular phenotypes consistent with these roles. We show that the distribution of these low-complexity proteins mirrors the distribution of I34-tRNAs in the phylogenetic tree.

SUBMITTER: Torres AG

PROVIDER: S-EPMC8266599 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundIn both prokaryotic and eukaryotic proteins, repeated occurrence of a single or a group of few amino acids are found. These regions are termed as low complexity regions (LCRs). It has been observed that amino acid bias in LCR is directly linked to their uncontrolled expansion and amyloid formation. But a comparative analysis of the behavior of LCR based on their constituent amino acids and their association with amyloidogenic propensity is not available.MethodsFirstly we grouped all LCRs on the basis of their composition: homo-polymers, positively charged amino acids, negatively charged amino acids, polar amino acids and hydrophobic amino acids. We analyzed the compositional pattern of LCRs in each group and their propensity to form amyloids. The functional characteristics of proteins containing different groups of LCRs were explored using DAVID. In addition, we also analyzed the classes, pathways and functions of human proteins that form amyloids in LCRs.ResultsAmong homopolymeric LCRs, the most common was Gln repeats. LCRs composed of repeats of Met and aromatic amino acids were amongst the least occurring. The results revealed that LCRs composed of negatively charged and polar amino acids were more common in comparison to LCRs formed by positively charged and hydrophobic amino acids. We also noted that generally proteins with LCRs were involved in transcription but those with Gly repeats were associated to translational activities. Our analysis suggests that proteins in which LCR is composed of hydrophobic residues are more prone toward amyloid formation. We also found that the human proteins with amyloid forming LCRs were generally involved in binding and catalytic activity.DiscussionThe presented analysis summarizes the most common and least occurring LCRs in proteins. Our results show that though repeats of Gln are the most abundant but Asn repeats make longest stretch of low complexity. The results showed that potential of LCRs to form amyloids varies with their amino acid composition.

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Human tRNAs with inosine 34 are essential to efficiently translate eukarya-specific low-complexity proteins.

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