ArticleThe Journal of biological chemistry2017
Adaptation of a Genetic Screen Reveals an Inhibitor for Mitochondrial Protein Import Component Tim44.
Article in The Journal of biological chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Cytosolic retention of HtrA2 during mitochondrial protein import stress triggers the DELE1-HRI pathway.Communications biology · 2024Article
- A first-in-class TIMM44 blocker inhibits bladder cancer cell growth.Cell death & disease · 2024Article
- The Interaction and Effect of a Small MitoBlock Library as Inhibitor of ALR Protein-Protein Interaction Pathway.International journal of molecular sciences · 2024Article
- Reduced Protein Import via TIM23 SORT Drives Disease Pathology in TIMM50-Associated Mitochondrial Disease.Molecular and cellular biology · 2024Article
- A two-step mitochondrial import pathway couples the disulfide relay with matrix complex I biogenesis.The Journal of cell biology · 2023Article
- The MitoLuc Assay System for Accurate Real-Time Monitoring of Mitochondrial Protein Import Within Mammalian Cells.Journal of molecular biology · 2023Article
- The mitochondrial protein TIMM44 is required for angiogenesis in vitro and in vivo.Cell death & disease · 2023Article
- TIMM44 is a potential therapeutic target of human glioma.Theranostics · 2022Article
- Targeting Mitochondrial Protein Expression as a Future Approach for Cancer Therapy.Frontiers in oncology · 2021Review
- MitoPlex: A targeted multiple reaction monitoring assay for quantification of a curated set of mitochondrial proteins.Journal of molecular and cellular cardiology · 2020Article
- Transport of Proteins into Mitochondria.The protein journal · 2019Review
- A High-Resolution Luminescent Assay for Rapid and Continuous Monitoring of Protein Translocation across Biological Membranes.Journal of molecular biology · 2019Article
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Authors and funding
9 authors.
Funding
Abstract
Diverse protein import pathways into mitochondria use translocons on the outer membrane (TOM) and inner membrane (TIM). We adapted a genetic screen, based on Ura3 mistargeting from mitochondria to the cytosol, to identify small molecules that attenuated protein import. Small molecule mitochondrial import blockers of the Carla Koehler laboratory (MB)-10 inhibited import of substrates that require the TIM23 translocon. Mutational analysis coupled with molecular docking and molecular dynamics modeling revealed that MB-10 binds to a specific pocket in the C-terminal domain of Tim44 of the protein-associated motor (PAM) complex. This region was proposed to anchor Tim44 to the membrane, but biochemical studies with MB-10 show that this region is required for binding to the translocating precursor and binding to mtHsp70 in low ATP conditions. This study also supports a direct role for the PAM complex in the import of substrates that are laterally sorted to the inner membrane, as well as the mitochondrial matrix. Thus, MB-10 is the first small molecule modulator to attenuate PAM complex activity, likely through binding to the C-terminal region of Tim44.
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