The structure of the human LACTB filament reveals the mechanisms of assembly and membrane binding.
Mitochondria are complex organelles that play a central role in metabolism. Dynamic membrane-associated processes regulate mitochondrial morphology and bioenergetics in response to cellular demand. In tumor cells, metabolic reprogramming requires active mitochondrial metabolism for providing key met...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2022-12-01
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| Series: | PLoS Biology |
| Online Access: | https://doi.org/10.1371/journal.pbio.3001899 |
| _version_ | 1797788341292236800 |
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| author | Jeremy A Bennett Lottie R Steward Johannes Rudolph Adam P Voss Halil Aydin |
| author_facet | Jeremy A Bennett Lottie R Steward Johannes Rudolph Adam P Voss Halil Aydin |
| author_sort | Jeremy A Bennett |
| collection | DOAJ |
| description | Mitochondria are complex organelles that play a central role in metabolism. Dynamic membrane-associated processes regulate mitochondrial morphology and bioenergetics in response to cellular demand. In tumor cells, metabolic reprogramming requires active mitochondrial metabolism for providing key metabolites and building blocks for tumor growth and rapid proliferation. To counter this, the mitochondrial serine beta-lactamase-like protein (LACTB) alters mitochondrial lipid metabolism and potently inhibits the proliferation of a variety of tumor cells. Mammalian LACTB is localized in the mitochondrial intermembrane space (IMS), where it assembles into filaments to regulate the efficiency of essential metabolic processes. However, the structural basis of LACTB polymerization and regulation remains incompletely understood. Here, we describe how human LACTB self-assembles into micron-scale filaments that increase their catalytic activity. The electron cryo-microscopy (cryoEM) structure defines the mechanism of assembly and reveals how highly ordered filament bundles stabilize the active state of the enzyme. We identify and characterize residues that are located at the filament-forming interface and further show that mutations that disrupt filamentation reduce enzyme activity. Furthermore, our results provide evidence that LACTB filaments can bind lipid membranes. These data reveal the detailed molecular organization and polymerization-based regulation of human LACTB and provide new insights into the mechanism of mitochondrial membrane organization that modulates lipid metabolism. |
| first_indexed | 2024-03-13T01:34:11Z |
| format | Article |
| id | doaj.art-b179e8a632c1452490b2d7a2da896ed5 |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-03-13T01:34:11Z |
| publishDate | 2022-12-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-b179e8a632c1452490b2d7a2da896ed52023-07-04T05:31:08ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852022-12-012012e300189910.1371/journal.pbio.3001899The structure of the human LACTB filament reveals the mechanisms of assembly and membrane binding.Jeremy A BennettLottie R StewardJohannes RudolphAdam P VossHalil AydinMitochondria are complex organelles that play a central role in metabolism. Dynamic membrane-associated processes regulate mitochondrial morphology and bioenergetics in response to cellular demand. In tumor cells, metabolic reprogramming requires active mitochondrial metabolism for providing key metabolites and building blocks for tumor growth and rapid proliferation. To counter this, the mitochondrial serine beta-lactamase-like protein (LACTB) alters mitochondrial lipid metabolism and potently inhibits the proliferation of a variety of tumor cells. Mammalian LACTB is localized in the mitochondrial intermembrane space (IMS), where it assembles into filaments to regulate the efficiency of essential metabolic processes. However, the structural basis of LACTB polymerization and regulation remains incompletely understood. Here, we describe how human LACTB self-assembles into micron-scale filaments that increase their catalytic activity. The electron cryo-microscopy (cryoEM) structure defines the mechanism of assembly and reveals how highly ordered filament bundles stabilize the active state of the enzyme. We identify and characterize residues that are located at the filament-forming interface and further show that mutations that disrupt filamentation reduce enzyme activity. Furthermore, our results provide evidence that LACTB filaments can bind lipid membranes. These data reveal the detailed molecular organization and polymerization-based regulation of human LACTB and provide new insights into the mechanism of mitochondrial membrane organization that modulates lipid metabolism.https://doi.org/10.1371/journal.pbio.3001899 |
| spellingShingle | Jeremy A Bennett Lottie R Steward Johannes Rudolph Adam P Voss Halil Aydin The structure of the human LACTB filament reveals the mechanisms of assembly and membrane binding. PLoS Biology |
| title | The structure of the human LACTB filament reveals the mechanisms of assembly and membrane binding. |
| title_full | The structure of the human LACTB filament reveals the mechanisms of assembly and membrane binding. |
| title_fullStr | The structure of the human LACTB filament reveals the mechanisms of assembly and membrane binding. |
| title_full_unstemmed | The structure of the human LACTB filament reveals the mechanisms of assembly and membrane binding. |
| title_short | The structure of the human LACTB filament reveals the mechanisms of assembly and membrane binding. |
| title_sort | structure of the human lactb filament reveals the mechanisms of assembly and membrane binding |
| url | https://doi.org/10.1371/journal.pbio.3001899 |
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