ArticleNature communications2021
Structures of the human LONP1 protease reveal regulatory steps involved in protease activation.
Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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Who cites it
54 citing papers in PubMed, 80 citations in OpenAlex.
- A selective inhibitor reveals roles for LONP1 in mitochondrial proteostasis and OXPHOS dependencies.Life science alliance · 2026Article
- Regulation of cellular proteostasis via mitochondrial protein import.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2026Review
- Higher-order structural organization of mitochondrial metabolism.The Journal of biological chemistry · 2026Review
- Reprogramming Mitochondrial Adaptation: LONP1 at the Crossroads of Proteostasis, Metabolism, and Disease.Antioxidants (Basel, Switzerland) · 2026Review
- Intracellular Activation of Dual-Pharmacophore Artezomib Enhances Selective Cytotoxicity in Hematologic Malignancies.Journal of medicinal chemistry · 2026Article
- Structural Analysis of Human LonP1 Protease Bound with the Native Substrate.Life (Basel, Switzerland) · 2026Article
- A post-translational regulatory map of chronic antigen-driven human T cell dysfunction.bioRxiv : the preprint server for biology · 2026Article
- Molecular mechanisms of mitochondrial AAA+ proteases.The Journal of biological chemistry · 2026Review
- LONP1 Variants Are Associated With Clinically Diverse Phenotypes.Clinical genetics · 2026Article
- Role of LONP1 in human diseases: molecular mechanisms and therapeutic potential.Cellular & molecular biology letters · 2026Review
- Cryo-EM structures of human ClpXP reveal mechanisms of assembly and proteolytic activation.Nature communications · 2026Article
- Inhibition of LONP1 in prostate cancer: bibliometrics-guided target screening and AI-driven antibody design.International journal of surgery (London, England) · 2026Article
- Loss of FBXO11 establishes a stem cell program in acute myeloid leukemia by dysregulating LONP1.The Journal of clinical investigation · 2026Article
- Lon peptidase 1 promotes proliferation and metastasis in breast cancer via interleukin 6 signaling.Discover oncology · 2025Article
- Substrate-dependent activation of LONP1 informs on proteolytic regulation and ATPase motor function.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Elastic analysis bridges structure and dynamics of an AAA+ molecular motor.PLoS computational biology · 2025Article
- Cryo-EM Reveals Regulatory Mechanisms Governing Substrate Selection and Activation of Human LONP1.bioRxiv : the preprint server for biology · 2025Article
- Quality control at the powerhouse: mitochondrial proteostasis dysfunction and disease.Biochemical Society transactions · 2025Article
- LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes.Nature metabolism · 2025Article
- AI-based quality assessment methods for protein structure models from cryo-EM.Current research in structural biology · 2025Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
The human mitochondrial AAA+ protein LONP1 is a critical quality control protease involved in regulating diverse aspects of mitochondrial biology including proteostasis, electron transport chain activity, and mitochondrial transcription. As such, genetic or aging-associated imbalances in LONP1 activity are implicated in pathologic mitochondrial dysfunction associated with numerous human diseases. Despite this importance, the molecular basis for LONP1-dependent proteolytic activity remains poorly defined. Here, we solved cryo-electron microscopy structures of human LONP1 to reveal the underlying molecular mechanisms governing substrate proteolysis. We show that, like bacterial Lon, human LONP1 adopts both an open and closed spiral staircase orientation dictated by the presence of substrate and nucleotide. Unlike bacterial Lon, human LONP1 contains a second spiral staircase within its ATPase domain that engages substrate as it is translocated toward the proteolytic chamber. Intriguingly, and in contrast to its bacterial ortholog, substrate binding within the central ATPase channel of LONP1 alone is insufficient to induce the activated conformation of the protease domains. To successfully induce the active protease conformation in substrate-bound LONP1, substrate binding within the protease active site is necessary, which we demonstrate by adding bortezomib, a peptidomimetic active site inhibitor of LONP1. These results suggest LONP1 can decouple ATPase and protease activities depending on whether AAA+ or both AAA+ and protease domains bind substrate. Importantly, our structures provide a molecular framework to define the critical importance of LONP1 in regulating mitochondrial proteostasis in health and disease.
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