Structural Insights into Metazoan Pretargeting GET Complexes

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2021 Dec 10

PMID 34887561

Citations 6

Authors

Alexander F A Keszei

Matthew C J Yip

Ta-Chien Hsieh

Sichen Shao

Affiliations

Soon will be listed here.

Abstract

Close coordination between chaperones is essential for protein biosynthesis, including the delivery of tail-anchored (TA) proteins containing a single C-terminal transmembrane domain to the endoplasmic reticulum (ER) by the conserved GET pathway. For successful targeting, nascent TA proteins must be promptly chaperoned and loaded onto the cytosolic ATPase Get3 through a transfer reaction involving the chaperone SGTA and bridging factors Get4, Ubl4a and Bag6. Here, we report cryo-electron microscopy structures of metazoan pretargeting GET complexes at 3.3-3.6 Å. The structures reveal that Get3 helix 8 and the Get4 C terminus form a composite lid over the Get3 substrate-binding chamber that is opened by SGTA. Another interaction with Get4 prevents formation of Get3 helix 4, which links the substrate chamber and ATPase domain. Both interactions facilitate TA protein transfer from SGTA to Get3. Our findings show how the pretargeting complex primes Get3 for coordinated client loading and ER targeting.

Citing Articles

A distinct dimer configuration of a diatom Get3 forming a tetrameric complex with its tail-anchored membrane cargo.

Chen C, Huang Y, Chan Y, Lin H, Lin H, Hsiao C BMC Biol. 2024; 22(1):136.

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A dual role of the conserved PEX19 helix in safeguarding peroxisomal membrane proteins.

Oh J, Kim D, Ahn S, Kim H, Cho H iScience. 2024; 27(4):109537.

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

Cho H, Liu Y, Chung S, Chandrasekar S, Weiss S, Shan S Nat Commun. 2024; 15(1):134.

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The GET insertase exhibits conformational plasticity and induces membrane thinning.

McDowell M, Heimes M, Enkavi G, Farkas A, Saar D, Wild K Nat Commun. 2023; 14(1):7355.

PMID: 37963916 PMC: 10646013. DOI: 10.1038/s41467-023-42867-2.

Proteotoxic stresses stimulate dissociation of UBL4A from the tail-anchored protein recognition complex.

Hagiwara T, Minami R, Ushio C, Yokota N, Kawahara H Biochem J. 2023; 480(19):1583-1598.

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