The pore conformation of lymphocyte perforin

DOI: 10.1126/sciadv.abk3147

Authors: Marina E. Ivanova (Birkbeck, University of London; Imperial College London) , Natalya Lukoyanova (Birkbeck, University of London) , Sony Malhotra (Birkbeck, University of London; Science and Technology Facilities Council) , Maya Topf (Birkbeck, University of London; Leibniz-Institut für Experimentelle Virologie and Universitätsklinikum Hamburg-Eppendorf (UKE)) , Joseph A. Trapani (Peter MacCallum Cancer Centr) , Ilia Voskoboinik (Peter MacCallum Cancer) , Helen R. Saibil (Birkbeck, University of London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Science Advances , VOL 8

State: Published (Approved)
Published: February 2022
Diamond Proposal Number(s): 14704

Abstract: Perforin is a pore-forming protein that facilitates rapid killing of pathogen-infected or cancerous cells by the immune system. Perforin is released from cytotoxic lymphocytes, together with proapoptotic granzymes, to bind to a target cell membrane where it oligomerizes and forms pores. The pores allow granzyme entry, which rapidly triggers the apoptotic death of the target cell. Here, we present a 4-Å resolution cryo–electron microscopy structure of the perforin pore, revealing previously unidentified inter- and intramolecular interactions stabilizing the assembly. During pore formation, the helix-turn-helix motif moves away from the bend in the central beta-sheet to form an intermolecular contact. Cryo–electron tomography shows that prepores form on the membrane surface with minimal conformational changes. Our findings suggest the sequence of conformational changes underlying oligomerization and membrane insertion, and explain how several pathogenic mutations affect function.

Subject Areas: Biology and Bio-materials, Medicine

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios I-Titan Krios I at Diamond

Other Facilities: EM facility at Birkbeck College

Added On: 28/03/2023 17:27

Documents:
sciadv.abk3147.pdf

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Cryo Electron Tomography (Cryo ET) Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)