Paul Schimmel, PhD
Professor
Department of Integrative Structural and Computational Biology
Research Focus
The genetic code was established over two billion years ago and became universally adopted by all living organisms. The rules of the code--which relate specific nucleotide triplets to specific amino acids--are established by aminoacylation reactions catalyzed by aminoacyl tRNA synthetases. In these reactions, an amino acid is associated with a specific nucleotide triplet of the genetic code, by virtue of being linked to a specific tRNA that harbors the anticodon triplet cognate to the amino acid. Because of their central role in establishing the rules of the code, the tRNAs are thought to have arisen quite early, perhaps in the context of an RNA world. The synthetases may have been amongst the earliest proteins to appear, perhaps replacing ribozymes that catalyzed the aminoacylation of primordial tRNAs. The Schimmel laboratory is interested in understanding all aspects of these systems.
Our present work focuses on the discovery of the large new biology that flows out of the tRNA synthetases. These enzymes are now known to be secreted, to have nuclear functions, and to pervade most or all parts of human biology with activities that are distinct from their catalytic function of charging tRNA. The laboratory uses methods and logic of molecular and cell biology, chemistry, and structural analysis to more deeply investigate these novel functions that have a fundamental role in maintaining organismal homeostasis, and in developing and regulating nervous, vascular, and immunological systems. The research is leading to the development of a broad new class of therapeutics to treat and cure human diseases.
Select Publications
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Kuhle, Bernhard; Hirschi, Marscha; Doerfel, Lili K.; Lander, Gabriel C.; Schimmel, Paul Structural basis for a degenerate tRNA identity code and the evolution of bimodal specificity in human mitochondrial tRNA recognition. Nature Communications 2023, 14, 4794.
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Cui, Haissi; Diedrich, Jolene K.; Wu, Douglas C.; Lim, Justin J J.; Nottingham, Ryan M.; Moresco, James J J.; Yates, John R.; Blencowe, Ben J.; Lambowitz, Alan M.; Schimmel, Paul Arg-tRNA synthetase links inflammatory metabolism to RNA splicing and nuclear trafficking via SRRM2. Nature Cell Biology 2023, 25, 592-603.
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Morodomi, Yosuke; Kanaji, Sachiko; Sullivan, Brian M.; Zarpellon, Alessandro; Orje, Je N.; Won, Eric; Shapiro, Ryan; Yang, Xiang- L.; Ruf, Wolfram; Schimmel, Paul; Ruggeri, Zaverio M.; Kanaji, Taisuke Inflammatory platelet production stimulated by tyrosyl-tRNA synthetase mimicking viral infection. PNAS 2022, 119, e2212659119.
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Kuhle, Bernhard; Hirschi, Marscha; Doerfel, Lili K.; Lander, Gabriel C.; Schimmel, Paul Structural basis for shape-selective recognition and aminoacylation of a D-armless human mitochondrial tRNA. Nature Communications 2022, 13, 5100.
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Cui, Haissi; Kapur, Mridu; Diedrich, Jolene K.; Yates, John R.; Ackerman, Susan L.; Schimmel, Paul Regulation of ex-translational activities is the primary function of the multi-tRNA synthetase complex. Nucleic Acids Research 2021, 3603-3616.
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Adams, Ryan A.; Fernandes-Cerqueira, Catia; Notarnicola, Antonella; Mertsching, Elisabeth; Xu, Zhiwen; Lo, Wing-sze; Ogilvie, Kathleen; Chiang, Kyle P.; Ampudia, Jeanette; Rosengren, Sanna; Cubitt, Andrea; King, David J.; Mendlein, John D.; Yang, Xiang-lei; Nangle, Leslie A.; Lundberg, Ingrid E.; Jakobsson, Per-johan; Schimmel, Paul Serum-circulating His-tRNA synthetase inhibits organ-targeted immune responses. Nature Cell Mol Immunol. 2021, 1463-1475.
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