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Cited by 16Mitochondrial Function and PathologyEnzyme Structure and FunctionAdvanced Electron Microscopy Techniques and Applications

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The structure of the human LACTB filament reveals the mechanisms of assembly and membrane binding

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Bennett, Jeremy A., Steward, Lottie R., Rudolph, Johannes, Voss, Adam P., Aydin, Halil·2022·PLOS Biology
DOI 10.1371/journal.pbio.3001899PMC PMC9815587

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Abstract

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.

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Figures

Fig 1 Human LACTB assembles into a filament. (A) Domain organization of full-length human LACTB and the construct used in the study. The color scheme is used throughout the manuscript. (B) Schematic diagram for recombinant expression and self-assembly of LACTB. (C) Coomassie-stained SDS-PAGE of purified LACTB filament. (D) Size-exclusion profile of WT LACTB using a Superose 6 column. SEC elution profile begins with the void volume (V0) of the column. (E) Representative negative-stain TEM image of purified samples containing high molecular weight species. Negative-stain TEM analysis is shown for the samples taken from the primary peak observed in the size-exclusion chromatogram and is highlighted with a red box in (C). Scale bar, 100 nm. (F) Activity of the purified LACTB filaments was determined by using a fluorescence-based assay with the error bars representing the SEM. Source data for (F) is provided in sheet Fig 1F in S1 Data. SEC, size-exclusion chromatography; SEM, standard error of the mean; TEM, transmission electron microscopy; WT, wild-type.
Fig 1 Human LACTB assembles into a filament. (A) Domain organization of full-length human LACTB and the construct used in the study. The color scheme is used throughout the manuscript. (B) Schematic diagram for recombinant expression and self-assembly of LACTB. (C) Coomassie-stained SDS-PAGE of purified LACTB filament. (D) Size-exclusion profile of WT LACTB using a Superose 6 column. SEC elution profile begins with the void volume (V0) of the column. (E) Representative negative-stain TEM image of purified samples containing high molecular weight species. Negative-stain TEM analysis is shown for the samples taken from the primary peak observed in the size-exclusion chromatogram and is highlighted with a red box in (C). Scale bar, 100 nm. (F) Activity of the purified LACTB filaments was determined by using a fluorescence-based assay with the error bars representing the SEM. Source data for (F) is provided in sheet Fig 1F in S1 Data. SEC, size-exclusion chromatography; SEM, standard error of the mean; TEM, transmission electron microscopy; WT, wild-type.CC BY · PubMed Central
Fig 2 CryoEM structure of human LACTB filament. (A) CryoEM images of helical LACTB filaments were processed to obtain the 3D reconstruction of the polymer. LACTB protomers are colored differently, and filament rise and twist are indicated. (B) Top view of the LACTB assembly with the indicated filament width and inner lumen diameter. (C) Ribbon diagram of LACTB monomer. The chain is colored in a rainbow gradient from N-terminus (blue) to C-terminus (red). Secondary structure elements of one protomer are labeled. (D) LACTB (residues 97 to 547) α-helices (cylinders), β-sheets (arrows), and loops (lines) are depicted in a topology diagram.
Fig 2 CryoEM structure of human LACTB filament. (A) CryoEM images of helical LACTB filaments were processed to obtain the 3D reconstruction of the polymer. LACTB protomers are colored differently, and filament rise and twist are indicated. (B) Top view of the LACTB assembly with the indicated filament width and inner lumen diameter. (C) Ribbon diagram of LACTB monomer. The chain is colored in a rainbow gradient from N-terminus (blue) to C-terminus (red). Secondary structure elements of one protomer are labeled. (D) LACTB (residues 97 to 547) α-helices (cylinders), β-sheets (arrows), and loops (lines) are depicted in a topology diagram.CC BY · PubMed Central
Fig 3 Structural characterization of LACTB dimerization interface. (A) LACTB protomers (colored in green and lilac) form an antiparallel dimer as shown in ribbon representation. Residues that are critical for oligomerization are represented in sticks. Black boxes indicate the position of dimer interface residues. (B) Zoomed in view of the black box in (A), showing the interactions that stabilize the dimer formation. The polar and charge–charge interactions are indicated by black and red dotted lines, respectively. (C) SEC elution profiles of WT and mutant LACTB. SEC elution profiles begin with the void volume (V0) of the column. Fractions were analyzed by SDS-PAGE and peak fractions used in negative-stain TEM analyses are highlighted with red boxes. Negative-stain TEM images demonstrate the polymerization activity of WT and mutant proteins. Scale bars, 100 nm. (D) Mutation of key residues involved in dimerization disrupts catalytic activity. Enzyme activity was determined in vitro by using a fluorescently labeled substrate and 3 independent experiments were performed for each sample. Bars represent the mean of at least 3 independent experiments and error bars represent the standard deviation. The underlying data in (D) is provided in sheet Fig 3D in S1 Data. SEC, size-exclusion chromatography; TEM, transmission electron microscopy; WT, wild-type.
Fig 3 Structural characterization of LACTB dimerization interface. (A) LACTB protomers (colored in green and lilac) form an antiparallel dimer as shown in ribbon representation. Residues that are critical for oligomerization are represented in sticks. Black boxes indicate the position of dimer interface residues. (B) Zoomed in view of the black box in (A), showing the interactions that stabilize the dimer formation. The polar and charge–charge interactions are indicated by black and red dotted lines, respectively. (C) SEC elution profiles of WT and mutant LACTB. SEC elution profiles begin with the void volume (V0) of the column. Fractions were analyzed by SDS-PAGE and peak fractions used in negative-stain TEM analyses are highlighted with red boxes. Negative-stain TEM images demonstrate the polymerization activity of WT and mutant proteins. Scale bars, 100 nm. (D) Mutation of key residues involved in dimerization disrupts catalytic activity. Enzyme activity was determined in vitro by using a fluorescently labeled substrate and 3 independent experiments were performed for each sample. Bars represent the mean of at least 3 independent experiments and error bars represent the standard deviation. The underlying data in (D) is provided in sheet Fig 3D in S1 Data. SEC, size-exclusion chromatography; TEM, transmission electron microscopy; WT, wild-type.CC BY · PubMed Central
Fig 4 Structural basis of LACTB filament assembly. (A) Ribbon diagram of LACTB tetramer. LACTB protomers are colored in green (A), lilac (B), orange (C), and pink (D). Residues that are critical for oligomerization are represented in sticks. Black boxes indicate the position of the residues located at both polymerization interfaces 1 and 2, respectively. (B and C) Zoomed in view of polymer interfaces 1 and 2, respectively, showing the interactions that facilitate the polymerization of human LACTB. The polar and charge–charge interactions are indicated by black and red dotted lines, respectively. (D) SEC elution profiles of WT and mutant LACTB. SEC elution profiles begin with the void volume (V0) of the column. Mutations to residues that are located at the polymerization interfaces 1 and 2 impair filamentation. Fractions were analyzed by SDS-PAGE and peak fractions used in negative-stain TEM analyses are highlighted with red boxes. Negative-stain TEM images demonstrate the polymerization activity of WT and mutant proteins. Scale bars, 100 nm. (E) Mutation of key residues involved in filament formation disrupts catalytic activity. Enzyme activity was determined in vitro by using a fluorescently labeled substrate and 3 independent experiments were performed for each sample. Bars represent the mean of at least 3 independent experiments and error bars represent the standard deviation. The source data from (E) is provided in sheet Fig 4E in S1 Data. SEC, size-exclusion chromatography; TEM, transmission electron microscopy; WT, wild-type.
Fig 4 Structural basis of LACTB filament assembly. (A) Ribbon diagram of LACTB tetramer. LACTB protomers are colored in green (A), lilac (B), orange (C), and pink (D). Residues that are critical for oligomerization are represented in sticks. Black boxes indicate the position of the residues located at both polymerization interfaces 1 and 2, respectively. (B and C) Zoomed in view of polymer interfaces 1 and 2, respectively, showing the interactions that facilitate the polymerization of human LACTB. The polar and charge–charge interactions are indicated by black and red dotted lines, respectively. (D) SEC elution profiles of WT and mutant LACTB. SEC elution profiles begin with the void volume (V0) of the column. Mutations to residues that are located at the polymerization interfaces 1 and 2 impair filamentation. Fractions were analyzed by SDS-PAGE and peak fractions used in negative-stain TEM analyses are highlighted with red boxes. Negative-stain TEM images demonstrate the polymerization activity of WT and mutant proteins. Scale bars, 100 nm. (E) Mutation of key residues involved in filament formation disrupts catalytic activity. Enzyme activity was determined in vitro by using a fluorescently labeled substrate and 3 independent experiments were performed for each sample. Bars represent the mean of at least 3 independent experiments and error bars represent the standard deviation. The source data from (E) is provided in sheet Fig 4E in S1 Data. SEC, size-exclusion chromatography; TEM, transmission electron microscopy; WT, wild-type.CC BY · PubMed Central
Fig 5 LACTB filaments bind to CL-enriched liposomes. (A–D) Representative negative-stain TEM images of LACTB filaments in the presence of liposomes. Scale bar, 100 nm. Purified LACTB filaments were incubated with CL-containing liposomes at room temperature for 4 h. Red boxes indicate protein–membrane contact sites. (E) Zoomed in views of the red boxes in (A–D), showing the details of protein–liposome interactions. (F) A schematic diagram of filament–liposome interactions illustrating different membrane-binding modes of LACTB filaments. (G) Catalytic activity of WT LACTB in the presence of liposomes. Enzyme activity was determined in vitro by using a fluorescently labeled substrate and 3 independent experiments were performed for each sample. Bars represent the mean of at least 3 independent WT and reconstitution assays. Error bars indicate standard deviation. (H) Liposome tethering activity of WT LACTB under the presence of liposomes of various compositions. Liposome tethering activity was quantified by counting 1,000 filaments from at least 3 independent reconstitution assays and calculating the total percentage of filament tethering. Bars represent the mean liposome tethering activity and error bars indicate SEM. (I) Liposome tethering activity of key residues involved in liposome binding. Liposome tethering activity was quantified by counting 1,000 filaments from at least 3 independent reconstitution assays and calculating the total percentage of filament tethering. Bars represent the mean liposome tethering activity of reconstitution assays and error bars indicate SEM. Statistical analysis was performed with an unpaired two-tailed Student t test (G) and unpaired two-tail Welch’s t tests (H, I). *p < 0.05, **p < 0.005, ns (no significance). The underlying data in (G), (H), and (I) are provided in sheets Fig 5G–5I in S1 Data. CL, cardiolipin; TEM, transmission electron microscopy; WT, wild-type.
Fig 5 LACTB filaments bind to CL-enriched liposomes. (A–D) Representative negative-stain TEM images of LACTB filaments in the presence of liposomes. Scale bar, 100 nm. Purified LACTB filaments were incubated with CL-containing liposomes at room temperature for 4 h. Red boxes indicate protein–membrane contact sites. (E) Zoomed in views of the red boxes in (A–D), showing the details of protein–liposome interactions. (F) A schematic diagram of filament–liposome interactions illustrating different membrane-binding modes of LACTB filaments. (G) Catalytic activity of WT LACTB in the presence of liposomes. Enzyme activity was determined in vitro by using a fluorescently labeled substrate and 3 independent experiments were performed for each sample. Bars represent the mean of at least 3 independent WT and reconstitution assays. Error bars indicate standard deviation. (H) Liposome tethering activity of WT LACTB under the presence of liposomes of various compositions. Liposome tethering activity was quantified by counting 1,000 filaments from at least 3 independent reconstitution assays and calculating the total percentage of filament tethering. Bars represent the mean liposome tethering activity and error bars indicate SEM. (I) Liposome tethering activity of key residues involved in liposome binding. Liposome tethering activity was quantified by counting 1,000 filaments from at least 3 independent reconstitution assays and calculating the total percentage of filament tethering. Bars represent the mean liposome tethering activity of reconstitution assays and error bars indicate SEM. Statistical analysis was performed with an unpaired two-tailed Student t test (G) and unpaired two-tail Welch’s t tests (H, I). *p < 0.05, **p < 0.005, ns (no significance). The underlying data in (G), (H), and (I) are provided in sheets Fig 5G–5I in S1 Data. CL, cardiolipin; TEM, transmission electron microscopy; WT, wild-type.CC BY · PubMed Central
Fig 6 The model of LACTB enables mapping the disease-associated mutations. (A) A schematic representation of full-length LACTB architecture. Residues 1–68 contain the predicted MTS and residues 243–290 form the flexible loop region. Residues that are associated with various human cancers are highlighted with a red dashed line. (B) Ribbon diagram of human LACTB tetramer. Protomers that form the tetramer are labeled A to D and colored as in Fig 4A. Mutations localizing to oligomerization interfaces are illustrated as sticks. Inset windows show the close-up views of oligomerization interfaces containing disease-associated mutations. Black boxes indicate the dimer and polymerization interfaces 1 and 2, respectively. MTS, mitochondrial targeting sequence.
Fig 6 The model of LACTB enables mapping the disease-associated mutations. (A) A schematic representation of full-length LACTB architecture. Residues 1–68 contain the predicted MTS and residues 243–290 form the flexible loop region. Residues that are associated with various human cancers are highlighted with a red dashed line. (B) Ribbon diagram of human LACTB tetramer. Protomers that form the tetramer are labeled A to D and colored as in Fig 4A. Mutations localizing to oligomerization interfaces are illustrated as sticks. Inset windows show the close-up views of oligomerization interfaces containing disease-associated mutations. Black boxes indicate the dimer and polymerization interfaces 1 and 2, respectively. MTS, mitochondrial targeting sequence.CC BY · PubMed Central

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Metadata

Authors
Bennett, J. A., Steward, L. R., Rudolph, J., Voss, A. P., & Aydin, H.
Affiliations
University of Colorado Boulder (US)
Corresponding author
Aydin, Halil
ORCID
Venue
PLOS Biology
Publisher
Public Library of Science (PLoS)
Published
2022-12-19
Volume
20
Issue
12
Pages
e3001899
ISSN
  • 1544-9173 (ISSN-L)
  • 1545-7885
DOI
10.1371/journal.pbio.3001899
PMC
PMC9815587
OpenAlex
W4311911807
Cited by
16
References
6
Citations by year
2026: 6 · 2025: 5 · 2024: 3 · 2023: 1 · 2022: 1
FWCI
0.82
Type
journal article
Language
en
Update notices
new_version (2023-01-05)
Open access
Licence
Locations
  • PLoS Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • CU Scholar (University of Colorado Boulder) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
University of Colorado Boulder
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Advanced Electron Microscopy Techniques and Applications
Keywords
LACTB, mitochondrial intermembrane space, protein filament assembly, membrane binding, mitochondrial lipid metabolism, tumor cell proliferation, enzyme activity
MeSH terms
Animals, beta-Lactamases, Cytoskeleton, Humans, Mammals, Membrane Proteins, Mitochondria, Neoplasms, Cryoelectron Microscopy, Mitochondrial Proteins

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