The pore conformation of lymphocyte perforin.
Marina E IvanovaNatalya LukoyanovaSony MalhotraAndriy KryshtafovychJoseph A TrapaniIlia VoskoboinikHelen R SaibilPublished in: Science advances (2022)
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 β 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.
Keyphrases
- electron microscopy
- molecular dynamics simulations
- single molecule
- molecular dynamics
- induced apoptosis
- peripheral blood
- cell death
- single cell
- cell cycle arrest
- dna binding
- cell therapy
- stem cells
- energy transfer
- candida albicans
- endoplasmic reticulum stress
- small molecule
- mass spectrometry
- bone marrow
- cell proliferation
- crystal structure