Journal
NATURE CHEMICAL BIOLOGY
Volume 16, Issue 6, Pages 653-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41589-020-0480-6
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Funding
- NIH [T32-HL007731, DP2 GM119139, R35-122603, P01-AG002132, R01-GM117593, P30-CA082103]
- UCSF Program in Breakthrough Biomedical Research - Sandler Foundation
- UCSF Program in Breakthrough Biomedical Research Postdoc Independent Research Grant - Sandler Foundation
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Defining the biologically active structures of proteins in their cellular environments remains challenging for proteins with multiple conformations and functions, where only a minor conformer might be associated with a given function. Here, we use deep mutational scanning to probe the structure and dynamics of alpha-synuclein, a protein known to adopt disordered, helical and amyloid conformations. We examined the effects of 2,600 single-residue substitutions on the ability of intracellularly expressed alpha-synuclein to slow the growth of yeast. Computational analysis of the data showed that the conformation responsible for this phenotype is a long, uninterrupted, amphiphilic helix with increasing dynamics toward the C terminus. Deep mutational scanning can therefore determine biologically active conformations in cellular environments, even for a highly dynamic multi-conformational protein.
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