6VFE

Gasdermin D pore

Summary for 6VFE

• Entry DOI: 10.2210/pdb6vfe/pdb
• EMDB information: 21160 21161
• Descriptor: Gasdermin-D, N-terminal (1 entity in total)
• Functional Keywords: pore-forming protein, lipid binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 33
• Total formula weight: 886057.29

Authors

Xia, S.,Ruan, J.,Wu, H. (deposition date: 2020-01-03, release date: 2021-04-21, Last modification date: 2024-05-29)

Primary citation

Xia, S.,Zhang, Z.,Magupalli, V.G.,Pablo, J.L.,Dong, Y.,Vora, S.M.,Wang, L.,Fu, T.M.,Jacobson, M.P.,Greka, A.,Lieberman, J.,Ruan, J.,Wu, H.
Gasdermin D pore structure reveals preferential release of mature interleukin-1.
Nature, 593:607-611, 2021

PubMed Abstract: As organelles of the innate immune system, inflammasomes activate caspase-1 and other inflammatory caspases that cleave gasdermin D (GSDMD). Caspase-1 also cleaves inactive precursors of the interleukin (IL)-1 family to generate mature cytokines such as IL-1β and IL-18. Cleaved GSDMD forms transmembrane pores to enable the release of IL-1 and to drive cell lysis through pyroptosis. Here we report cryo-electron microscopy structures of the pore and the prepore of GSDMD. These structures reveal the different conformations of the two states, as well as extensive membrane-binding elements including a hydrophobic anchor and three positively charged patches. The GSDMD pore conduit is predominantly negatively charged. By contrast, IL-1 precursors have an acidic domain that is proteolytically removed by caspase-1. When permeabilized by GSDMD pores, unlysed liposomes release positively charged and neutral cargoes faster than negatively charged cargoes of similar sizes, and the pores favour the passage of IL-1β and IL-18 over that of their precursors. Consistent with these findings, living-but not pyroptotic-macrophages preferentially release mature IL-1β upon perforation by GSDMD. Mutation of the acidic residues of GSDMD compromises this preference, hindering intracellular retention of the precursor and secretion of the mature cytokine. The GSDMD pore therefore mediates IL-1 release by electrostatic filtering, which suggests the importance of charge in addition to size in the transport of cargoes across this large channel.

PubMed: 33883744
DOI: 10.1038/s41586-021-03478-3

Experimental method

ELECTRON MICROSCOPY (3.9 Å)