8D9X

Cryo-EM structure of human DELE1 in oligomeric form

Summary for 8D9X

• Entry DOI: 10.2210/pdb8d9x/pdb
• EMDB information: 27269
• Descriptor: Maltodextrin-binding protein,DAP3-binding cell death enhancer 1 short form (1 entity in total)
• Functional Keywords: oligomer, mitochondria, integrated stress response, kinase, tetratricopeptide repeat, protein binding
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 586750.69

Authors

Yang, J.,Lander, G.C. (deposition date: 2022-06-11, release date: 2023-06-14, Last modification date: 2023-09-20)

Primary citation

Yang, J.,Baron, K.R.,Pride, D.E.,Schneemann, A.,Guo, X.,Chen, W.,Song, A.S.,Aviles, G.,Kampmann, M.,Luke Wiseman, R.,Lander, G.C.
DELE1 oligomerization promotes integrated stress response activation.
Nat.Struct.Mol.Biol., 30:1295-1302, 2023

PubMed Abstract: Mitochondria are dynamic organelles that continually respond to cellular stress. Recent studies have demonstrated that mitochondrial stress is relayed from mitochondria to the cytosol by the release of a proteolytic fragment of DELE1 that binds to the eIF2α kinase HRI to initiate integrated stress response (ISR) signaling. We report the cryo-electron microscopy structure of the C-terminal cleavage product of human DELE1, which assembles into a high-order oligomer. The oligomer consists of eight DELE1 monomers that assemble with D symmetry via two sets of hydrophobic inter-subunit interactions. We identified the key residues involved in DELE1 oligomerization, and confirmed their role in stabilizing the octamer in vitro and in cells using mutagenesis. We further show that assembly-impaired DELE1 mutants are compromised in their ability to induce HRI-dependent ISR activation in cell culture models. Together, our findings provide molecular insights into the activity of DELE1 and how it signals to promote ISR activity following mitochondrial insult.

PubMed: 37550454
DOI: 10.1038/s41594-023-01061-0

Experimental method

ELECTRON MICROSCOPY (3.8 Å)