BAK core dimers bind lipids and can be bridged by them

Cowan, A.D.; Smith, Nicholas A.; Sandow, Jarrod J.; Kapp, Eugene A.; Rustam, Yepy H.; Murphy, James M.; Brouwer, J.M.; Bernardini, Jonathan P.; Roy, Michael J; Wardak, Ahmad; Tan, Iris; Webb, Andrew I.; Gulbis, Jacqueline M.; Smith, Brian J.; Reid, Gavin E.; Dewson, Grant; Colman, Peter M.; Czabotar, P.E.

doi:10.1038/s41594-020-0494-5

Cited by 58 publications

(89 citation statements)

References 60 publications

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“…Binding of a BH3 domain causes partial unfolding and opening of the hinge region (middle, PDB: 4U2U [ 66 ]), which leads to the formation of a membrane-binding domain-swapped dimer (right, PDB: 4U2V [ 66 ]). Panel C is based on [ 67 ]. The two chains in the BAK dimer are coloured grey and orange.…”

Section: Resultsmentioning

confidence: 99%

Crystal and solution structures reveal oligomerization of individual capsid homology domains of Drosophila Arc

et al. 2021

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Synaptic plasticity is vital for brain function and memory formation. One of the key proteins in long-term synaptic plasticity and memory is the activity-regulated cytoskeleton-associated protein (Arc). Mammalian Arc forms virus-like capsid structures in a process requiring the N-terminal domain and contains two C-terminal lobes that are structural homologues to retroviral capsids. Drosophila has two isoforms of Arc, dArc1 and dArc2, with low sequence similarity to mammalian Arc, but lacking a large N-terminal domain. Both dArc isoforms are related to the Ty3/gypsy retrotransposon capsid, consisting of N- and C-terminal lobes. Structures of dArc1, as well as capsids formed by both dArc isoforms, have been recently determined. We carried out structural characterization of the four individual dArc lobe domains. As opposed to the corresponding mammalian Arc lobe domains, which are monomeric, the dArc lobes were all oligomeric in solution, indicating a strong propensity for homophilic interactions. A truncated N-lobe from dArc2 formed a domain-swapped dimer in the crystal structure, resulting in a novel dimer interaction that could be relevant for capsid assembly or other dArc functions. This domain-swapped structure resembles the dimeric protein C of flavivirus capsids, as well as the structure of histones dimers, domain-swapped transcription factors, and membrane-interacting BAK domains. The strong oligomerization properties of the isolated dArc lobe domains explain the ability of dArc to form capsids in the absence of any large N-terminal domain, in contrast to the mammalian protein.

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Section: Resultsmentioning

confidence: 99%

Crystal and solution structures reveal oligomerization of individual capsid homology domains of Drosophila Arc

et al. 2021

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show abstract

“…Binding of a BH3 domain causes partial unfolding and opening of the hinge region (middle, PDB: 4U2U [65]), which leads to the formation of the membrane-binding domain-swapped dimer (right, PDB: 4U2V [65]). Panel C is based on [66]. The two chains in the BAK dimer are coloured grey and orange.…”

Section: Resultsmentioning

confidence: 99%

“…The core domain then dimerizes to form amphipathic domain-swapped dimers [65,74]. These dimers can then further oligomerize and partition to the outer mitochondrial membrane where they bind and cause permeabilization, leading to the release of apoptosis factors such as cytochrome c into the cytosol [66]. Both the inactive and active forms of BAK show strikingly similar fold topology to the monomeric and dimeric state of the dArc2-NL, respectively.…”

Section: Resultsmentioning

confidence: 99%

Crystal and solution structures reveal oligomerization of individual capsid homology domains of Drosophila Arc

Hallin

Markússon

Böttger

et al. 2020

Preprint

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Synaptic plasticity is vital for brain function and memory formation. One of the key proteins in long-term synaptic plasticity and memory is the activity-regulated cytoskeleton-associated protein (Arc). Mammalian Arc forms virus-like capsid-like structures in a process requiring the N-terminal domain and contains two C-terminal lobes that are structural homologues to retroviral capsids. Drosophila has two isoforms of Arc, dArc1 and dArc2, with low sequence similarity to mammalian Arc, but lacking the mammalian Arc N-terminal domain. Both dArc isoforms have a capsid homology domain consisting of N- and C-terminal lobes. We carried out structural characterization of the four individual dArc lobe domains. As opposed to the corresponding mammalian Arc lobe domains, which are monomeric, the dArc lobes were all oligomeric in solution, indicating a strong propensity for homophilic interactions. The N-lobe from dArc2 formed a domain-swapped dimer in the crystal structure, resulting in a novel dimer interaction that could be relevant for capsid assembly or other dArc functions. This domain-swapped structure resembles the dimeric protein C of flavivirus capsids, as well as the structure of histones dimers, domain-swapped transcription factors, and membrane-interacting BAK domains. The strong oligomerization properties of the isolated dArc lobe domains explain the ability of dArc to form capsids in the absence of any large N-terminal domain, in contrast to the mammalian protein.

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“…In this scenario, the energy cost of the membrane perturbations (perhaps including initial pore opening) induced by the insertion of BAX dimers into the membrane could be reduced by the coalescence of these membrane alterations and associated BAX/BAK molecules. Such a model would explain the higher‐order assembly of BAX/BAK dimers via membrane‐mediated interactions (Harroun et al , 1999; Reynwar et al , 2007; Shlomovitz & Gov, 2009; Cowan et al , 2020) and provide a mechanistic basis for the pore growth observed during apoptosis (Riley et al , 2018; Flores‐Romero & García‐Sáez, 2020).…”

Section: Pore Formation In Membranes Is a Conserved Strategy To Kill mentioning

confidence: 99%

Pore formation in regulated cell death

2020

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The discovery of alternative signaling pathways that regulate cell death has revealed multiple strategies for promoting cell death with diverse consequences at the tissue and organism level. Despite the divergence in the molecular components involved, membrane permeabilization is a common theme in the execution of regulated cell death. In apoptosis, the permeabilization of the outer mitochondrial membrane by BAX and BAK releases apoptotic factors that initiate the caspase cascade and is considered the point of no return in cell death commitment. Pyroptosis and necroptosis also require the perforation of the plasma membrane at the execution step, which involves Gasdermins in pyroptosis, and MLKL in the case of necroptosis. Although BAX/BAK, Gasdermins and MLKL share certain molecular features like oligomerization, they form pores in different cellular membranes via distinct mechanisms. Here, we compare and contrast how BAX/BAK, Gasdermins, and MLKL alter membrane permeability from a structural and biophysical perspective and discuss the general principles of membrane permeabilization in the execution of regulated cell death.

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BAK core dimers bind lipids and can be bridged by them

Cited by 58 publications

References 60 publications

Crystal and solution structures reveal oligomerization of individual capsid homology domains of Drosophila Arc

Crystal and solution structures reveal oligomerization of individual capsid homology domains of Drosophila Arc

Crystal and solution structures reveal oligomerization of individual capsid homology domains of Drosophila Arc

Pore formation in regulated cell death

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