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...

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Published in:	PLoS biology Vol. 20; no. 12; p. e3001899
Main Authors:	Bennett, Jeremy A, Steward, Lottie R, Rudolph, Johannes, Voss, Adam P, Aydin, Halil
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 19-12-2022 Public Library of Science (PLoS)
Subjects:	Animals Assembly beta-Lactamases - genetics Bioenergetics Biology and Life Sciences Biosynthesis Breast cancer Catalytic activity Cell growth Cell proliferation Cryoelectron Microscopy Cytology Cytoskeleton - metabolism Enzymatic activity Enzyme activity Enzymes Filamentation Filaments Gene expression Homeostasis Humans Lipid membranes Lipid metabolism Lipids Mammals - metabolism Membrane proteins Membrane Proteins - metabolism Membranes Metabolism Metabolites Mitochondria Mitochondria - metabolism Mitochondrial Proteins - metabolism Morphology Mutation Neoplasms - metabolism Organelles Physical Sciences Physiological aspects Physiological research Polymerization Protein turnover Proteins Research and Analysis Methods Structure Tumor cells Tumorigenesis Tumors β Lactamase United States
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Summary:	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.
Bibliography:	new_version ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The authors have declared that no competing interests exist.
ISSN:	1545-7885 1544-9173 1545-7885
DOI:	10.1371/journal.pbio.3001899