{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:26:59Z","timestamp":1792787219526,"version":"4.5.0"},"reference-count":69,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,7,16]],"date-time":"2024-07-16T00:00:00Z","timestamp":1721088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>Faithful mRNA decoding depends on the accuracy of aminoacyl-tRNA synthetases (ARSs). Aminoacyl-tRNA proofreading mechanisms have been well-described in bacteria, humans, and plants. However, our knowledge of translational fidelity in protozoans is limited. <jats:italic>Trypanosoma brucei<\/jats:italic> (<jats:italic>Tb<\/jats:italic>) is a eukaryotic, protozoan pathogen that causes Human African Trypanosomiasis, a fatal disease if untreated. <jats:italic>Tb<\/jats:italic> undergoes many physiological changes that are dictated by nutrient availability throughout its insect-mammal lifecycle. In the glucose-deprived insect vector, the tsetse fly, <jats:italic>Tb<\/jats:italic> use proline to make ATP via mitochondrial respiration. Alanine is one of the major by-products of proline consumption. We hypothesize that the elevated alanine pool challenges <jats:italic>Tb<\/jats:italic> prolyl-tRNA synthetase (ProRS), an ARS known to misactivate alanine in all three domains of life, resulting in high levels of misaminoacylated Ala-tRNA<jats:sup>Pro<\/jats:sup>. <jats:italic>Tb<\/jats:italic> encodes two domains that are members of the INS superfamily of aminoacyl-tRNA deacylases. One homolog is appended to the N-terminus of <jats:italic>Tb<\/jats:italic> ProRS, and a second is the major domain of multi-aminoacyl-tRNA synthetase complex (MSC)-associated protein 3 (MCP3). Both ProRS and MCP3 are housed in the <jats:italic>Tb<\/jats:italic> MSC. Here, we purified <jats:italic>Tb<\/jats:italic> ProRS and MCP3 and observed robust Ala-tRNA<jats:sup>Pro<\/jats:sup> deacylation activity from both enzymes <jats:italic>in vitro<\/jats:italic>. Size-exclusion chromatography multi-angle light scattering used to probe the oligomerization state of MCP3 revealed that although its unique N-terminal extension confers homodimerization in the absence of tRNA, the protein binds to tRNA as a monomer. Kinetic assays showed MCP3 alone has relaxed tRNA specificity and promiscuously hydrolyzes cognate Ala-tRNA<jats:sup>Ala<\/jats:sup>; this activity is significantly reduced in the presence of <jats:italic>Tb<\/jats:italic> alanyl-tRNA synthetase, also housed in the MSC. Taken together, our results provide insight into translational fidelity mechanisms in <jats:italic>Tb<\/jats:italic> and lay the foundation for exploring MSC-associated proteins as novel drug targets.<\/jats:p>","DOI":"10.3389\/fmicb.2024.1445687","type":"journal-article","created":{"date-parts":[[2024,7,16]],"date-time":"2024-07-16T04:49:26Z","timestamp":1721105366000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Trypanosoma brucei multi-aminoacyl-tRNA synthetase complex formation limits promiscuous tRNA proofreading"],"prefix":"10.3389","volume":"15","author":[{"given":"Rylan R.","family":"Watkins","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Vradi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Shulgina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Musier-Forsyth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,7,16]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"29763","DOI":"10.1074\/jbc.274.42.29763","article-title":"The procyclin repertoire of Trypanosoma brucei. 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