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The cryo-EM structure of the acid activatable pore-forming immune effector Macrophage-expressed gene 1

Author

Listed:
  • Siew Siew Pang

    (Monash University
    Monash University)

  • Charles Bayly-Jones

    (Monash University
    Monash University)

  • Mazdak Radjainia

    (Monash University
    Thermo Fischer Scientific)

  • Bradley A. Spicer

    (Monash University
    Monash University)

  • Ruby H. P. Law

    (Monash University
    Monash University)

  • Adrian W. Hodel

    (University College London
    University College London)

  • Edward S. Parsons

    (University College London)

  • Susan M. Ekkel

    (Monash University
    Monash University)

  • Paul J. Conroy

    (Monash University
    Monash University)

  • Georg Ramm

    (Monash University)

  • Hariprasad Venugopal

    (Monash University)

  • Phillip I. Bird

    (Monash University)

  • Bart W. Hoogenboom

    (University College London
    University College London
    University College London)

  • Ilia Voskoboinik

    (Peter MacCallum Cancer Centre
    The University of Melbourne)

  • Yann Gambin

    (University of New South Wales
    University of New South Wales)

  • Emma Sierecki

    (University of New South Wales
    University of New South Wales)

  • Michelle A. Dunstone

    (Monash University
    Monash University)

  • James C. Whisstock

    (Monash University
    Monash University
    EMBL Australia, Monash University
    Australian National University)

Abstract

Macrophage-expressed gene 1 (MPEG1/Perforin-2) is a perforin-like protein that functions within the phagolysosome to damage engulfed microbes. MPEG1 is thought to form pores in target membranes, however, its mode of action remains unknown. We use cryo-Electron Microscopy (cryo-EM) to determine the 2.4 Å structure of a hexadecameric assembly of MPEG1 that displays the expected features of a soluble prepore complex. We further discover that MPEG1 prepore-like assemblies can be induced to perforate membranes through acidification, such as would occur within maturing phagolysosomes. We next solve the 3.6 Å cryo-EM structure of MPEG1 in complex with liposomes. These data reveal that a multi-vesicular body of 12 kDa (MVB12)-associated β-prism (MABP) domain binds membranes such that the pore-forming machinery of MPEG1 is oriented away from the bound membrane. This unexpected mechanism of membrane interaction suggests that MPEG1 remains bound to the phagolysosome membrane while simultaneously forming pores in engulfed bacterial targets.

Suggested Citation

  • Siew Siew Pang & Charles Bayly-Jones & Mazdak Radjainia & Bradley A. Spicer & Ruby H. P. Law & Adrian W. Hodel & Edward S. Parsons & Susan M. Ekkel & Paul J. Conroy & Georg Ramm & Hariprasad Venugopal, 2019. "The cryo-EM structure of the acid activatable pore-forming immune effector Macrophage-expressed gene 1," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
  • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12279-2
    DOI: 10.1038/s41467-019-12279-2
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    Cited by:

    1. Anaïs Menny & Marie V. Lukassen & Emma C. Couves & Vojtech Franc & Albert J. R. Heck & Doryen Bubeck, 2021. "Structural basis of soluble membrane attack complex packaging for clearance," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    2. Alexander Harjung & Alessandro Fracassi & Neal K. Devaraj, 2024. "Encoding extracellular modification of artificial cell membranes using engineered self-translocating proteins," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    3. Guendalina Marini & Brad Poland & Chris Leininger & Natalya Lukoyanova & Dan Spielbauer & Jennifer K. Barry & Dan Altier & Amy Lum & Eric Scolaro & Claudia Pérez Ortega & Nasser Yalpani & Gary Sandahl, 2023. "Structural journey of an insecticidal protein against western corn rootworm," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    4. Fang Jiao & François Dehez & Tao Ni & Xiulian Yu & Jeremy S. Dittman & Robert Gilbert & Christophe Chipot & Simon Scheuring, 2022. "Perforin-2 clockwise hand-over-hand pre-pore to pore transition mechanism," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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