Autoinhibition of dimeric NINJ1 prevents plasma membrane rupture.

ABSTRACT: Lytic cell death culminates in plasma membrane rupture, which releases large intracellular molecules to augment the inflammatory response. Plasma membrane rupture is mediated by the effector membrane protein ninjurin-1 (NINJ1)¹, which polymerizes and ruptures the membrane via its hydrophilic face^1-4. How NINJ1 is restrained under steady-state conditions to ensure cell survival remains unknown. Here we describe the molecular underpinnings of NINJ1 inhibition. Using cryogenic electron microscopy, we determined the structure of inactive-state mouse NINJ1 bound to the newly developed nanobody Nb538. Inactive NINJ1 forms a face-to-face homodimer by adopting a three-helix conformation with unkinked transmembrane helix 1 (TM1), in contrast to the four-helix TM1-kinked active

SUBMITTER: Pourmal S 

PROVIDER: S-EPMC11711097 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature