University of Illinois at Urbana-Champaign
Susan Martinis, Steven Blanke, Jie Chen, Lin-Feng Chen, Raven Huang, Zaida Luthey-Schulten
Aminoacyl-tRNA synthetases (AARSs) constitute a group of enzymes whose primary function is to translate the nucleotide codes contained in genes into their corresponding amino acids, the building-blocks of proteins. Because AARSs are essential for the translation of genetic information into proteins, they are found in all forms of life. University of Illinois researchers propose to determine the structures and characterize the functions of newly discovered genetic variants of these enzymes in humans that function in pathways other than translation. Using twenty mammalian leucyl-tRNA synthetases (LeuRS) as a model, the PIs will create a unique platform that can be used to systematically interrogate the function of over 250 AARS variants identified to date. This platform will consist of cutting-edge biochemical and cell based assays to determine variant localization and function(s). The platform will also include computational methodologies for structure-function analyses, as well as sophisticated intracellular investigations. Recent studies indicate that AARS genes can produce proteins whose functions vary from an acute inflammatory response to cholesterol transport. One already identified alternate function for a LeuRS variant is in cancer cell proliferation and inhibitors of this variant are being considered as cancer therapeutics. The project’s impact is expected to be broad as the team will likely uncover new mechanisms for how proteins acquire alternate functions.
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