Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Feb 18;7(1):17.
doi: 10.3390/biom7010017.

Sulfur Modifications of the Wobble U 34 in tRNAs and Their Intracellular Localization in Eukaryotic Cells

Affiliations
Free PMC article
Review

Sulfur Modifications of the Wobble U 34 in tRNAs and Their Intracellular Localization in Eukaryotic Cells

Yumi Nakai et al. Biomolecules. .
Free PMC article

Abstract

The wobble uridine (U34) of transfer RNAs (tRNAs) for two-box codon recognition, i.e., tRNALysUUU, tRNAGluUUC, and tRNAGlnUUG, harbor a sulfur- (thio-) and a methyl-derivative structure at the second and fifth positions of U34, respectively. Both modifications are necessary to construct the proper anticodon loop structure and to enable them to exert their functions in translation. Thio-modification of U34 (s²U34) is found in both cytosolic tRNAs (cy-tRNAs) and mitochondrial tRNAs (mt-tRNAs). Although l-cysteine desulfurase is required in both cases, subsequent sulfur transfer pathways to cy-tRNAs and mt-tRNAs are different due to their distinct intracellular locations. The s²U34 formation in cy-tRNAs involves a sulfur delivery system required for the biosynthesis of iron-sulfur (Fe/S) clusters and certain resultant Fe/S proteins. This review addresses presumed sulfur delivery pathways for the s²U34 formation in distinct intracellular locations, especially that for cy-tRNAs in comparison with that for mt-tRNAs.

Keywords: cluster; cytosolic tRNA (cy-tRNA); iron-sulfur (Fe/S); mitochondrial tRNA (mt-tRNA); the wobble uridine (U34); thio-modification of U34 (s2U34).

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Sulfur-containing small molecules. Many biocofactors such as thiamine, iron-sulfur (Fe/S) clusters, and molybdenum cofactor (MoCo) contain sulfur atoms in their structure (upper column). Various sulfur-containing nucleosides are also identified. For example, the 2-thiocytidine derivatives are 2-thiocytidine (s2C) found in bacteria and 2-thio-2′-O-methyluridine (s2Um) found in humans. 4-thiouridine (s4U) is found in bacteria. Various types of the hyper-modified uridine, such as 5-carboxymethylaminomethyl-2-thiouridine (cmnm5s2U), 5-methylaminomethyl-2-thiouridine (mnm5s2U), 5-taurinomethyl-2-thiouridine (τm5s2U), and 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U) are found at U34. Various methylthio-adenosine derivatives, such as 2-methylthio- N6-isopentenyladenosine (ms2i6A) and 2-methylthio-N6-threonylcarbamoyladenosine (ms2t6A), are also found in both bacteria and eukaryotes. Sulfur atoms incorporated into the molecule in the biosynthetic pathway are shown with circles.
Figure 2
Figure 2
Involvement of the l-cysteine desulfurase Nfs1 in transfer RNA (tRNA) modification and iron-sulfur (Fe/S) cluster biosynthesis in Saccharomyces cerevisiae. The l-cysteine desulfurase Nfs1, identified as a member of the iron-sulfur cluster biogenesis (so-called “ISC”) proteins, is essential for the biogenesis of s2U34 in both cytosolic transfer RNAs (cy-tRNAs) and mitochondrial transfer RNAs (mt-tRNAs). Mtu1 is a mitochondrial tRNA-specific 2-thiouridylase. Comparing to the case of humans, existence of the cytosolic Nfs1 and the dual location of Tum1 are unclear in yeast (see text in detail). Cytosolic Fe/S protein maturation requires mitochondrial Nfs1 and the cytosolic iron-sulfur cluster assembly (so-called “CIA”) proteins, Cfd1, Nbp35, and Cia1. A putative unknown sulfur carrier to be exported from mitochondria via a membrane-bound protein Atm1 is shown as X. Elongator complex function as a dimer of the complex of Elongator complex 1-6 (ELP1-6) proteins, and function in the C5 modification (marked with a star) of U34. Both a cytosolic ubiquitin-like protein (UBL), ubiquitin-related modifier 1 (Urm1), and its partner sulfurtransferase, ubiquitin-activating enzyme-like protein 4 (Uba4), are required for the formation of s2U34 in cy-tRNAs. Ncs6 and Ncs2 are also involved in the s2U34 formation in cy-tRNAs. The sulfur atoms delivered to the iron-sulfur (Fe/S) clusters and s2U34 in both mitochondrial (mt-) and cytosolic (cy-) tRNAs are shown with filled circles. Fe atoms of Fe/S clusters are shown with filled squares. See text in detail.
Figure 3
Figure 3
The UBL—ubiquitin-activating enzyme (E1)-like protein system related to the thio-modification of cytosolic transfer RNA (tRNA). The protein modifier system of ubiquitination found in eukaryotes (upper column) is compared with a plausible model for the sulfur transfer between Uba4 and Urm1, which is for the s2U34 formation in yeast cytosolic tRNA (lower column). In the ubiquitination pathway, ubiquitin (Ub) is first bound to the UBA protein E1 (a sulfhydryl of an active cysteine residue is shown in a yellow circle) and then, after several reactions, is finally bound to form a thioester bond. In the thio-modification pathway, a UBL protein Urm1 is first bound to the partner UBA protein, Uba4. A complex of Ncs6 and Ncs2 (the Ncs6/Ncs2 complex) is thought to be involved in the last step of the tRNA recognition and thio-modification of cy-tRNAs. Sulfur atoms transferred in this system are shown with filled circles.
Figure 4
Figure 4
Sulfur delivery to the U34 in cy-tRNAs and for molybdopterin (MPT) biosynthesis in eukaryotes. Multicellular eukaryotes (human and plant) possess two types of ubiquitin-like (UBL proteins, for MoCo biosynthesis, and for the thio-modification of tRNA, both of which associate with the common Uba4/MOCS3-type UBA proteins (left panel). On the other hand, the yeast Saccharomyces cerevisiae contains no MoCo biosynthesis-related proteins and only Urm1 for thio-modification of tRNAs associates to Uba4 (right panel). Sulfur atoms to be delivered are shown with filled circles.

Similar articles

See all similar articles

Cited by 4 articles

References

    1. Machnicka M.A., Milanowska K., Osman Oglou O., Purta E., Kurkowska M., Olchowik A., Januszewski W., Kalinowski S., Dunin-Horkawicz S., Rother K.M., et al. MODOMICS: A database of RNA modification pathways—2013 update. Nucleic Acids Res. 2013;41:D262–D267. doi: 10.1093/nar/gks1007. - DOI - PMC - PubMed
    1. El Yacoubi B., Bailly M., de Crécy-Lagard V. Biosynthesis and function of posttranscriptional modification of transfer RNAs. Annu. Rev. Genet. 2012;46:69–95. doi: 10.1146/annurev-genet-110711-155641. - DOI - PubMed
    1. Jackman J.E., Alfonzo J.D. Transfer RNA modifications: Nature’s combinatorial chemistry playground. Wiley Interdiscip. Rev RNA. 2013;4:35–48. doi: 10.1002/wrna.1144. - DOI - PMC - PubMed
    1. Hopper A.K. Transfer RNA post-transcriptional processing, turnover, and subcellular dynamics in the yeast Saccharomyces cerevisiae. Genetics. 2013;194:43–67. doi: 10.1534/genetics.112.147470. - DOI - PMC - PubMed
    1. Lauhon C.T., Kambampati R. The iscS gene in Escherichia coli is required for the biosynthesis of 4-thiouridine, thiamin, and NAD. J. Biol. Chem. 2000;275:20096–20103. doi: 10.1074/jbc.M002680200. - DOI - PubMed
Feedback