Dynamic stability of Sgt2 enables selective and privileged client handover in a chaperone triad

Hyunju Cho, Yumeng Liu, Sang Yoon Chung, Sowmya Chandrasekar, Shimon Weiss, Shu ou Shan

Research output: Contribution to journalArticlepeer-review

Abstract

Membrane protein biogenesis poses acute challenges to protein homeostasis, and how they are selectively escorted to the target membrane is not well understood. Here we address this question in the guided-entry-of-tail-anchored protein (GET) pathway, in which tail-anchored membrane proteins (TAs) are relayed through an Hsp70-Sgt2-Get3 chaperone triad for targeting to the endoplasmic reticulum. We show that the Hsp70 ATPase cycle and TA substrate drive dimeric Sgt2 from a wide-open conformation to a closed state, in which TAs are protected by both substrate binding domains of Sgt2. Get3 is privileged to receive TA from closed Sgt2, whereas off-pathway chaperones remove TAs from open Sgt2. Sgt2 closing is less favorable with suboptimal GET substrates, which are rejected during or after the Hsp70-to-Sgt2 handover. Our results demonstrate how fine-tuned conformational dynamics in Sgt2 enable hydrophobic TAs to be effectively funneled onto their dedicated targeting factor while also providing a mechanism for substrate selection.

Original languageEnglish
Article number134
JournalNature Communications
Volume15
Issue number1
DOIs
StatePublished - Dec 2024

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© 2024, The Author(s).

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