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The mechanism of membrane-associated steps in tail-anchored protein insertion

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  • Malaiyalam Mariappan

    (Cell Biology and Metabolism Program, National Institute of Child Health and Human Development, National Institutes of Health, Room 101, Building 18T, 18 Library Drive, Bethesda, Maryland 20892, USA)

  • Agnieszka Mateja

    (The University of Chicago, Gordon Center for Integrative Science, Room W238, 929 East 57th Street, Chicago, Illinois 60637, USA)

  • Malgorzata Dobosz

    (The University of Chicago, Gordon Center for Integrative Science, Room W238, 929 East 57th Street, Chicago, Illinois 60637, USA)

  • Elia Bove

    (The University of Chicago, Gordon Center for Integrative Science, Room W238, 929 East 57th Street, Chicago, Illinois 60637, USA)

  • Ramanujan S. Hegde

    (Cell Biology and Metabolism Program, National Institute of Child Health and Human Development, National Institutes of Health, Room 101, Building 18T, 18 Library Drive, Bethesda, Maryland 20892, USA
    Present address: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.)

  • Robert J. Keenan

    (The University of Chicago, Gordon Center for Integrative Science, Room W238, 929 East 57th Street, Chicago, Illinois 60637, USA)

Abstract

Tail-anchored (TA) membrane proteins destined for the endoplasmic reticulum are chaperoned by cytosolic targeting factors that deliver them to a membrane receptor for insertion. Although a basic framework for TA protein recognition is now emerging, the decisive targeting and membrane insertion steps are not understood. Here we reconstitute the TA protein insertion cycle with purified components, present crystal structures of key complexes between these components and perform mutational analyses based on the structures. We show that a committed targeting complex, formed by a TA protein bound to the chaperone ATPase Get3, is initially recruited to the membrane through an interaction with Get2. Once the targeting complex has been recruited, Get1 interacts with Get3 to drive TA protein release in an ATPase-dependent reaction. After releasing its TA protein cargo, the now-vacant Get3 recycles back to the cytosol concomitant with ATP binding. This work provides a detailed structural and mechanistic framework for the minimal TA protein insertion cycle.

Suggested Citation

  • Malaiyalam Mariappan & Agnieszka Mateja & Malgorzata Dobosz & Elia Bove & Ramanujan S. Hegde & Robert J. Keenan, 2011. "The mechanism of membrane-associated steps in tail-anchored protein insertion," Nature, Nature, vol. 477(7362), pages 61-66, September.
    • Handle: RePEc:nat:nature:v:477:y:2011:i:7362:d:10.1038_nature10362
    DOI: 10.1038/nature10362
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    Cited by:

    1. Melanie A. McDowell & Michael Heimes & Giray Enkavi & Ákos Farkas & Daniel Saar & Klemens Wild & Blanche Schwappach & Ilpo Vattulainen & Irmgard Sinning, 2023. "The GET insertase exhibits conformational plasticity and induces membrane thinning," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Hyunju Cho & Yumeng Liu & SangYoon Chung & Sowmya Chandrasekar & Shimon Weiss & Shu-ou Shan, 2024. "Dynamic stability of Sgt2 enables selective and privileged client handover in a chaperone triad," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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