ArticleNature communications2026
Cryo-EM structures of human ClpXP reveal mechanisms of assembly and proteolytic activation.
Article in Nature communications, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Pharmacological inhibition of CLPP stabilizes LETMD1 to boost thermogenesis and alleviate obesity.Adipocyte · 2026Article
- Targeting ClpP Protease: Emerging Therapeutic Strategies and Small-Molecule Modulators in Drug Discovery.Medicinal research reviews · 2026Review
- CLPX acquires an iron-sulfur cluster to sustain mitochondrial proteostasis in cancer cells.Nature communications · 2026Article
- DM: a simple solution to suppress air-water interface interactions in cryo-EM.bioRxiv : the preprint server for biology · 2026Article
- Molecular mechanisms of mitochondrial AAA+ proteases.The Journal of biological chemistry · 2026Review
- A mitochondrial insertion directs substrate selection and engagement by ClpX.bioRxiv : the preprint server for biology · 2026Article
- Development and evaluation of mitochondria-targeted caseinolytic protease (ClpP) agonist chemical probes in in vitro breast cancer models.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Article
- Structural insights into the Pseudomonas aeruginosa ClpP1•ClpP2 heterocomplex and its interactions with the AAA+ ClpX unfoldase.Protein science : a publication of the Protein Society · 2025Article
- Allosteric regulation of proteolytic machines unveiled by the synergy between cryo-EM and solution NMR spectroscopy.The Biochemical journal · 2025Review
- Mechanism of allosteric activation in human mitochondrial ClpP protease.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
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3 authors.
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Abstract
The human ClpXP complex (hClpXP) orchestrates mitochondrial protein quality control through targeted degradation of misfolded and unnecessary proteins. While bacterial ClpXP systems are well characterized, the assembly and regulation of human ClpXP remain poorly understood. In this study, we elucidate the complete assembly pathway of hClpXP through high-resolution cryo-electron microscopy (cryo-EM) structures. Our findings confirm that hClpP exists as a single-ring heptamer in isolation and reveal a previously undocumented initial assembly complex in which hexameric hClpX first engages with heptameric hClpP. We further demonstrate how this interaction drives substantial conformational rearrangements that facilitate the formation of tetradecameric hClpP within the fully assembled complex. Notably, we characterize a unique eukaryotic sequence in hClpX, termed the E-loop, which plays a critical role in stabilizing hexamer assembly and maintaining ATPase activity. Additionally, we show that peptide binding at the hClpP active site triggers further structural changes essential for achieving full proteolytic competence. Together, these structures provide unprecedented mechanistic insights into the stepwise assembly and activation of hClpXP, significantly advancing our understanding of this essential mitochondrial protein degradation machinery.
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