title: Multiple selection filters ensure accurate tail-anchored membrane protein targeting.
abstract: Accurate protein localization is crucial to generate and maintain organization in all cells. Achieving accuracy is challenging, as the molecular signals that dictate a protein's cellular destination are often promiscuous. A salient example is the targeting of an essential class of tail-anchored (TA) proteins, whose sole defining feature is a transmembrane domain near their C-terminus. Here we show that the Guided Entry of Tail-anchored protein (GET) pathway selects TA proteins destined to the endoplasmic reticulum (ER) utilizing distinct molecular steps, including differential binding by the co-chaperone Sgt2 and kinetic proofreading after ATP hydrolysis by the targeting factor Get3. Further, the different steps select for distinct physicochemical features of the TA substrate. The use of multiple selection filters may be general to protein biogenesis pathways that must distinguish correct and incorrect substrates based on minor differences.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, United States.
authors.forename: Meera
authors.initials: M
authors.lastname: Rao
authors.affiliation: Howard Hughes Medical Institute, University of California, San Francisco, United States.|Department of Biochemistry and Biophysics, University of California, San Francisco, United States.
authors.forename: Voytek
authors.initials: V
authors.lastname: Okreglak
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, United States.
authors.forename: Un Seng
authors.initials: US
authors.lastname: Chio
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, United States.
authors.forename: Hyunju
authors.initials: H
authors.lastname: Cho
authors.affiliation: Howard Hughes Medical Institute, University of California, San Francisco, United States.|Department of Biochemistry and Biophysics, University of California, San Francisco, United States.
authors.forename: Peter
authors.identifier: 0000-0002-6849-708X
authors.initials: P
authors.lastname: Walter
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, United States.
authors.forename: Shu-Ou
authors.identifier: 0000-0002-6526-1733
authors.initials: SO
authors.lastname: Shan
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006868:Hydrolysis; D008565:Membrane Proteins / Q000378:metabolism*; D021381:Protein Transport; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D020662:Guanine Nucleotide Exchange Factors; D008565:Membrane Proteins; D029701:Saccharomyces cerevisiae Proteins; C520576:Sgt2 protein, S cerevisiae; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; C529048:Get3 protein, S cerevisiae
keywords: ATPase; S. cerevisiae; biochemistry; biological fidelity; cell biology; fluorescence spectroscopy; guided entry of tail anchored proteins; protein targeting and translocation