Mechanistic basis for a molecular triage reaction

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Science  20 Jan 2017:
Vol. 355, Issue 6322, pp. 298-302
DOI: 10.1126/science.aah6130

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Deciding a protein's fate

Protein synthesis inside cells is finely balanced with protein degradation to maintain homeostasis. Shao et al. show how differential affinities and binding kinetics of three chaperones regulate the fate of tail-anchored (TA) membrane proteins. The chaperone SGTA binds to TA proteins and quickly transfers them to the targeting factor TRC40 through the C-terminal domain of the quality-control module BAG6. Proteins that dissociate from SGTA can either rebind or, at a slower rate, be bound by the C-terminal domain of BAG6. The latter puts them on a path to degradation. This hierarchy means that biosynthesis has the higher priority, but excess free TA proteins are degraded.

Science, this issue p. 298


Newly synthesized proteins are triaged between biosynthesis and degradation to maintain cellular homeostasis, but the decision-making mechanisms are unclear. We reconstituted the core reactions for membrane targeting and ubiquitination of nascent tail-anchored membrane proteins to understand how their fate is determined. The central six-component triage system is divided into an uncommitted client-SGTA complex, a self-sufficient targeting module, and an embedded but self-sufficient quality control module. Client-SGTA engagement of the targeting module induces rapid, private, and committed client transfer to TRC40 for successful biosynthesis. Commitment to ubiquitination is dictated primarily by comparatively slower client dissociation from SGTA and nonprivate capture by the BAG6 subunit of the quality control module. Our results provide a paradigm for how priority and time are encoded within a multichaperone triage system.

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