دورية أكاديمية
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Robust Sequence Determinants of α-Synuclein Toxicity in Yeast Implicate Membrane Binding.

التفاصيل البيبلوغرافية
العنوان: Robust Sequence Determinants of α-Synuclein Toxicity in Yeast Implicate Membrane Binding.
المؤلفون: Newberry RW; Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143, United States., Arhar T; Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, California 94143, United States., Costello J; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Hartoularos GC; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Maxwell AM; Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, California 94143, United States., Naing ZZC; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Pittman M; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Reddy NR; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Schwarz DMC; Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, California 94143, United States., Wassarman DR; Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, California 94143, United States., Wu TS; Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, California 94143, United States., Barrero D; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Caggiano C; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Catching A; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Cavazos TB; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Estes LS; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Faust B; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Fink EA; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Goldman MA; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Gomez YK; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Gordon MG; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Gunsalus LM; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Hoppe N; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Jaime-Garza M; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Johnson MC; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Jones MG; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Kung AF; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Lopez KE; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Lumpe J; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Martyn C; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., McCarthy EE; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Miller-Vedam LE; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Navarro EJ; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Palar A; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Pellegrino J; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Saylor W; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Stephens CA; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Strickland J; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Torosyan H; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Wankowicz SA; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Wong DR; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Wong G; Integrative Program in Quantitative Biology, University of California, San Francisco, California 94143, United States., Redding S; Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143, United States., Chow ED; Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143, United States., DeGrado WF; Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143, United States., Kampmann M; Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143, United States.; Institute for Neurodegenerative Disease, University of California, San Francisco, California 94143, United States.; Chan Zuckerberg Biohub, San Francisco, California 94158, United States.
المصدر: ACS chemical biology [ACS Chem Biol] 2020 Aug 21; Vol. 15 (8), pp. 2137-2153. Date of Electronic Publication: 2020 Aug 12.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 101282906 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1554-8937 (Electronic) Linking ISSN: 15548929 NLM ISO Abbreviation: ACS Chem Biol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, D.C. : American Chemical Society, c2006-
مواضيع طبية MeSH: Saccharomyces cerevisiae/*drug effects , alpha-Synuclein/*toxicity, Amino Acid Sequence ; Humans ; Mutation ; Parkinson Disease/metabolism ; Protein Conformation ; Saccharomyces cerevisiae/metabolism ; alpha-Synuclein/chemistry ; alpha-Synuclein/genetics
مستخلص: Protein conformations are shaped by cellular environments, but how environmental changes alter the conformational landscapes of specific proteins in vivo remains largely uncharacterized, in part due to the challenge of probing protein structures in living cells. Here, we use deep mutational scanning to investigate how a toxic conformation of α-synuclein, a dynamic protein linked to Parkinson's disease, responds to perturbations of cellular proteostasis. In the context of a course for graduate students in the UCSF Integrative Program in Quantitative Biology, we screened a comprehensive library of α-synuclein missense mutants in yeast cells treated with a variety of small molecules that perturb cellular processes linked to α-synuclein biology and pathobiology. We found that the conformation of α-synuclein previously shown to drive yeast toxicity-an extended, membrane-bound helix-is largely unaffected by these chemical perturbations, underscoring the importance of this conformational state as a driver of cellular toxicity. On the other hand, the chemical perturbations have a significant effect on the ability of mutations to suppress α-synuclein toxicity. Moreover, we find that sequence determinants of α-synuclein toxicity are well described by a simple structural model of the membrane-bound helix. This model predicts that α-synuclein penetrates the membrane to constant depth across its length but that membrane affinity decreases toward the C terminus, which is consistent with orthogonal biophysical measurements. Finally, we discuss how parallelized chemical genetics experiments can provide a robust framework for inquiry-based graduate coursework.
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معلومات مُعتمدة: P01 AG002132 United States AG NIA NIH HHS; T32 EB009383 United States EB NIBIB NIH HHS; F31 CA243439 United States CA NCI NIH HHS; U54 CA209891 United States CA NCI NIH HHS; R25 GM056847 United States GM NIGMS NIH HHS; R01 GM117593 United States GM NIGMS NIH HHS; F31 HG011007 United States HG NHGRI NIH HHS; T32 GM008284 United States GM NIGMS NIH HHS; T32 GM067547 United States GM NIGMS NIH HHS; DP2 GM119139 United States GM NIGMS NIH HHS; T32 HL007731 United States HL NHLBI NIH HHS; R35 GM122603 United States GM NIGMS NIH HHS; F31 CA232325 United States CA NCI NIH HHS; T32 GM064337 United States GM NIGMS NIH HHS
المشرفين على المادة: 0 (alpha-Synuclein)
تواريخ الأحداث: Date Created: 20200814 Date Completed: 20210506 Latest Revision: 20210822
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC7442712
DOI: 10.1021/acschembio.0c00339
PMID: 32786289
قاعدة البيانات: MEDLINE
الوصف
تدمد:1554-8937
DOI:10.1021/acschembio.0c00339