9I6F

Cryo-EM structure of HIGD2A bound complex IV

9I6F の概要

• エントリーDOI: 10.2210/pdb9i6f/pdb
• EMDBエントリー: 52613 52654
• 分子名称: HIG1 domain family member 2A, mitochondrial, Cytochrome c oxidase subunit 6C, Cytochrome c oxidase subunit 7A2, mitochondrial, ... (21 entities in total)
• 機能のキーワード: human mitochondria, respirasome complex, assembly, cytochrome c oxidase, complex iv, higd2a, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 14
• 化学式量合計: 246121.64

構造登録者

Nguyen, M.D.,Rorbach, J.,Singh, V. (登録日: 2025-01-30, 公開日: 2025-12-03, 最終更新日: 2026-01-21)

主引用文献

Nguyen, M.D.,Sierra-Magro, A.,Singh, V.,Khawaja, A.,Timon-Gomez, A.,Barrientos, A.,Rorbach, J.
Structural basis for late maturation steps of mitochondrial respiratory chain complex IV within the human respirasome.
Nat Commun, 2026

PubMed Abstract: The mitochondrial respiratory chain comprises four multimeric complexes (CI-CIV) that drive oxidative phosphorylation by transferring electrons to oxygen and generating the proton gradient required for ATP synthesis. These complexes can associate into supercomplexes (SCs), such as the CI + CIII₂ + CIV respirasome, but how SCs form, by joining preassembled complexes or by engaging partially assembled intermediates, remains unresolved. Here, we use cryo-electron microscopy to determine high-resolution structures of native human CI + CIII₂ + CIV late-assembly intermediates. Together with biochemical analyses, these structures show that respirasome biogenesis concludes with the final maturation of CIV while it is associated with fully assembled CI and CIII₂. We identify HIGD2A as a placeholder factor within isolated and supercomplexed CIV that is replaced by subunit NDUFA4 during the last step of CIV and respirasome assembly. This mechanism suggests that placeholders such as HIGD2A act as molecular timers, preventing premature incorporation of NDUFA4 or its isoforms and ensuring the orderly progression of pre-SC particles into functional respirasomes. Since defects in CIV assembly, including NDUFA4 deficiencies, cause severe encephalomyopathies and neurodegenerative disorders, understanding the molecular architecture and assembly pathways of isolated and supercomplexed CIV offers insight into the pathogenic mechanisms underlying these conditions.

PubMed: 41519940
DOI: 10.1038/s41467-025-68274-3

実験手法

ELECTRON MICROSCOPY (2.95 Å)