University of Washington
Judit Villen, Stanley Fields, William Noble
New DNA-sequencing methods have led to the discovery of millions of mutations that change the encoded protein sequences, but the impact of nearly all of these mutations on protein function is unknown. Current approaches that analyze the effects of mutations are inadequate, as they rely on computational predictions whose accuracy is questionable, or they interrogate only one protein at a time and thus would require hundreds of years to interpret existing data. To overcome this critical bottleneck, a team of investigators at the University of Washington seeks to develop Limited Mistranslation Mutagenesis (LMM). LMM is a technology that combines non-genetic mutagenesis with biochemical assays and mass spectrometry to assess the functional effects of amino acid substitutions on a proteome-wide basis in a timeframe of just days. LMM will generate the first mutational sensitivity maps that span the entire proteome, revealing deleterious amino acid substitutions that directly impact protein functions. These maps will provide an invaluable resource for biologists, serving as an essential companion guide to genome sequences. Development of this technology and resource will impact basic biology, by accelerating our knowledge of how proteins act; protein engineering, by guiding the design of novel proteins with enhanced properties; and genomics, by allowing the interpretation of millions of human mutations and establishing their relevance to disease..
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